Expandable gastroretentive dosage form

ABSTRACT

An oral gastro-retentive delivery device is provided which unfolds rapidly upon contact with gastric juice. The device is configured in a collapsed configuration for oral intake and unfolding for gastric retention for a predetermined period of time and eventually reducing in size for passage through the rest of the GI track.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S. patentapplication Ser. No. 14/728,986, filed on Jun. 2, 2015, which claims thebenefit of and priority to U.S. Provisional Application Ser. No.62/006,541, filed on Jun. 2, 2014 and U.S. Provisional Application Ser.No. 62/093,763, filed on Dec. 18, 2014, the entire contents of which areincorporated herein by reference.

FIELD OF THE DISCLOSURE

The present disclosure relates to a pharmaceutical product. Moreparticularly, the present disclosure relates to an oral pharmaceuticalor gastric retentive dosage form and formulations relating thereto.

BACKGROUND

There has been extensive research in the area of gastric retentive drugdelivery systems and dosage forms. These systems and dosage forms areparticularly useful for the delivery of drugs that:

-   -   (1) have a “narrow absorption window” in the gastrointestinal        tract, for example, drugs that are preferentially absorbed in        the duodenum and/or jejunum over ileum and/or colon, or have        better solubility in upper parts of the gastrointestinal tract        (GI);    -   (2) are intended for local treatment of proximal parts of the        gastrointestinal tract (stomach and/or duodenum); and/or    -   (3) degrade in the colon or in the intestines, etc.

Gastric retentive drug delivery systems or dosage forms have focusedresearch in three areas of technology: namely, floating systems; systemswith expanding geometry through swelling or unfolding; and bioadhesivesystems.

The general concept of the expandable gastroretentive systems and dosageforms is that the system or dosage form starts in a condition orconfiguration suitable for swallowing. The system or dosage form thenexpands in the stomach to prevent gastric emptying. Eventually, thesystem or dosage form reduces in size to pass through the pylorus ordisintegrates. Some of the original formulations with this approach areknown from the veterinary world. For example, U.S. Pat. No. 3,844,285discloses the concept of a pill that can be swallowed with wings tapeddown that eventually expand once water-degradable tape disintegrates.Such veterinary gastroretentive devices and formulations are sold underthe tradenames Captec® and Ivomec® SR Bolus. In the area ofcommercialized animal products, Paratect Flex® bolus is a trilaminatesheet with a central polymeric matrix and drug load which is rolled upand held by a piece of water-soluble adhesive tape in the form of acylindrical pill.

In the area of human oral application, U.S. Pat. No. 5,002,772 disclosesa device with a plurality of compressible retention arms attached to acontrolled release device which, in the expanded configuration, resistsgastrointestinal transit. U.S. Pat. Nos. 4,735,804 and 4,767,627disclose a series of substantially planar geometric shapes, e.g., atetrahedron formed of a bioerodible polymer that may be compressed andcollapsed for oral administration. U.S. Pat. No. 8,298,574 discloses an“Accordion pill”, a sheet with a length of more than 20 mm, folded likean accordion and placed in a capsule.

There have been many challenges in designing gastric retentive dosageforms relating to ability to scale up/manufacture/assemble, drug loadingcapacity, retention during fasted state, the inclusion of an emergencyrelease mechanism to expel the delivery system or dosage form in anemergency situation, using pharmaceutically acceptable ingredients etc.Improvements concerning any one of these challenges would provide asignificant contribution to the area of gastric retentive drug deliverysystems and dosage forms.

SUMMARY OF THE DISCLOSURE

Improvements concerning any one of these challenges and needs wouldprovide a significant contribution to the area of gastric retentive drugdelivery systems and dosage forms. The present disclosure relates to agastroretentive dosage form (GRDF) that includes one or more of thefollowing characteristics:

-   -   Rapidly unfolds within less than 3 min. to maximum gastric        retentive size;    -   Maintains a sufficient size integrity and rigidity throughout        the time period under gastric physiology or conditions; and/or    -   Delays gastric emptying for a specific time dependent on the        extent of API

According to an aspect of the present disclosure a gastroretentivedosage form (GRDF) for extended retention in a stomach is provided whichincludes: a body configured to transform between a collapsedconfiguration for ingestion, an expanded configuration for retentionwithin the stomach and a third configuration wherein after apredetermined time period has elapsed, the GRDF disassembles into two ormore parts such that each of the disassembled parts of the GRDF is sizedfor exiting the stomach; and an active pharmaceutical ingredient (API)or diagnostic. In aspects, the third configuration is induced by atleast a partial release of the API or diagnostic or compositionsthereof.

In any of the aspects described herein, the body is configured totransform between a collapsed configuration for ingestion and anexpanded configuration suitable for gastric retention within less than 5minutes, in aspects, less than 4 minutes, in aspects, less than 3minutes. In aspects described herein, a method is provided for gastricretention wherein a GRDF transforms to an expanded configuration forgastric retention within less than 5 minutes, in aspects, less than 4minutes, in aspects, less than 3 minutes. Once the capsule at leastpartially dissolves, the body automatically transitions to the expandedconfiguration.

In any of the aspects, after a pre-determined period of time, the GRDFsdescribed herein will eventually lose their mechanical integrity as asingle unit, disassemble and pass from the stomach for subsequentevacuation. There are many possible mechanisms to achieve this result,all of which are encompassed by the present disclosure.

In any of the aspects described herein, the predetermined period of timeis more than about 4 hours, in aspects, more than about 6 hours, inaspects, more than about 7 hours, in aspects more than 12 hours, inaspects more than 24 hs.

In any of the aspects described herein, transforming to the thirdconfiguration occurs when more than 70% of the active pharmaceuticalingredient is released, in aspects, when more than 75% of the activepharmaceutical ingredient is released, in aspects, when more than 80% ofthe active pharmaceutical ingredient is released, in aspects, when morethan 85% of the active pharmaceutical ingredient is released, inaspects, when more than 90% of the active pharmaceutical ingredient isreleased, in aspects, when more than 95% of the active pharmaceuticalingredient is released, in aspects, when 100% of the activepharmaceutical ingredient is released.

It should be understood that any method or mechanism that is configuredto transition or open the GRDF to the expanded configuration isencompassed by the present disclosure.

In one aspect, a superporous hydrogel system may be incorporated intothe inner part of the arms which expands upon exposure to the gastricenvironment thereby forcing the two arms apart and to the expandedconfiguration. In another aspect, a leaf spring (similar to thosedescribed above) springs outwards and extends from the inner area of oneor both of the arms once the expanding configuration is initiated oronce the mechanical integrity of the collapsed condition has beencompromised, e.g., capsule is dissolved. In other aspects, variousmechanisms may be employed to lock the arms in an expanded configurationuntil the insert has sufficiently erodes to disassemble the GRDF.

For example, in any of the aspects described herein, an inner facingsurface of one of the arms may include a locking mechanism to lock theleaf spring in place in the expanded configuration. Alternatively and inaddition to the hinge assemblies described above, the hinge assembly mayinclude one or more mechanical interfaces or mechanisms, gear, spring,cam, etc. that are configured to maintain or lock the GRDF in anexpanded configuration until disassembly. In aspects, the leaf springmay simply be configured to bias the GRDF from the collapsedconfiguration and not necessarily lock to maintain the GRDF in theexpanded configuration but may be configured to simply prevent the GRDFfrom transitioning back to the collapsed configuration.

In any of the aspects described herein, the leaf spring or biasingmechanism may be configured to lock the two arms in the expandedconfiguration until disassembly. One or more locking mechanisms may beemployed for this purpose, or, alternatively, the leaf spring may beconfigured to engage one of the arms to keep the two arms apart untildisassembly. In other aspects, the biasing mechanism, e.g., leaf spring,may be configured to engage the opposing arm to keep the two arms andseparated as the insert slowly erodes. As the insert erodes (API isreleased), the bias of the leaf spring gradually lessens or the leafspring regresses into the arm such that the angle β between the two armsand lessens to a point when the size or formation (e.g., triangularshape) of the GRDF is small enough to pass through the pyloric valve inthe stomach. As can be appreciated, in this instance the GRDF does notnecessarily need to disassembly for it to safely pass through thepyloric valve.

In any of the aspects described herein, the GRDF further comprises abiasing element configured to maintain the two arms apart once the twoarms transition to the expanded configuration. In aspects, the biasingelement is configured to transition the two arms from the collapsedconfiguration.

In aspects according to the present disclosure, the body may include atleast two arms, or in other aspects, two arms. In any of the aspectsdescribed herein, two arms are capable of providing a size relevant forgastric retention. In any of the aspects described herein, the GRDFfurther comprises a biasing element configured to maintain the two armsapart once the two arms transition to the expanded configuration. Inaspects, the biasing element is configured to transition the two armsfrom the collapsed configuration. Once in expanded position, the lengthbetween the tips of two arms is about 26-30 mm in length.

In aspects described herein, the biasing element forms part of the hingeassembly.

In any of the aspects described herein a size of at least one of the twoarms is substantially maintained during transition betweenconfigurations. For example, even after 24 hr exposure to simulatedgastric fluids—there is less than 10% preferably less than 5% change inweight, length and thickness of each arm, hinge etc.

In any of the aspects described herein, one of the at least two armsincludes a cavity defined therein configured to engage the hingeassembly and the API or diagnostic or composition thereof. In any of theaspects described herein, at least a portion of the hinge assembly, maybe sandwiched between at least one of the at least two arms of the bodyand the API or diagnostic or composition thereof hold one and other inplace. Thus, any erosion or partial release of any of the API or APIcomposition, the hinge assembly, arm or diagnostic will result inrelease from expanded state or end of gastric retention. For example,the hinge assembly, may be configured to disengage from the at least onearm upon partial release of the API. In another example, the hinge, APIor arm may be coated or partially comprise a pH or temperature sensitivepolymer which may be caused to erode via change in environment.

In any of the aspects described herein, in the expanded configuration,the at least two arms define an interior angle between about 45 degreesand about 90 degrees, in aspects, the at least two arms define aninterior angle between about 45 degrees and about 80 degrees. In any ofthe aspects described herein, in the expanded configuration, the atleast two arms define an interior angle of less than about 90°therebetween.

In any of the aspects described herein, at least one of the at least twoarms may be configured to releasably engage the API or diagnostic. Inany of the aspects described herein, the API or diagnostic is positionedwithin a cavity defined in the body. In any of the aspects describedherein, the API may be positioned within the cavity in the form of acomposition. The cavity may be formed for example, using injectionmolding, 3D printing, etc. In any of the aspects described herein, theat least two arms may be pivotably connected together or in articulatedrelationship by a hinge assembly and may be configured to disengage fromone another due to partial degradation of at least one of the at leasttwo arms or hinge assembly or partial release of the API or diagnostic.The partial degradation of at least one of the at least two arms orhinge assembly or partial release the API or diagnostic may be due to apH dependent polymer. In any of the aspects described herein, the pHdependent polymer may be configured to erode in a basic environment.

In any of the aspects described herein, the API or diagnostic is encasedor positioned within a cavity within the at least one of the at leasttwo arms.

In any of the aspects described herein, the API or diagnostic isreleased via an opening defined within at least one of the two arms.

In any of the aspects described herein, the API or diagnostic is in theform of an insert tablet shaped to fit within a cavity defined in atleast one of the at least two arms.

In any of the aspects described herein, the GRDFs are designed tomaximize the volume and/or weight ratio of API to total excipients, inan effort to maximize the drug volume and/or weight load to be processedin the stomach while minimizing the volume of non-drug material thatmust pass through the gastrointestinal tract although any relevantamount of API is encompassed by the present disclosure. According to oneaspect of the disclosure, a ratio of the weight of the activepharmaceutical ingredients to the weight of total excipients is fromabout 0.8 to about 0.05, in embodiments, from about 0.7 to about 0.3,and in other embodiment, from about 0.6 to about 0.4 or 0.5 to about0.95. According to one aspect of the disclosure, a ratio of the weightof excipient to the weight of the API or the diagnostic is from about0.8 to about 0.05, in embodiments, from about 0.7 to about 0.3, and inother embodiment, from about 0.6 to about 0.4. The total excipients mayinclude the arms, the hinge, the excipients in the insert, and thecapsule. In embodiments, the load of the excipients may be from about500 mg to about 2000 mg. In any of the aspects described herein, theamount of API present in the insert may be an amount greater than 400mg, 600 mg, 800 mg, 1000 mg, or 1500 mg. Alternatively, in aspects, theAPI drug load is about 400 milligrams to about 1.5 grams, in aspects,the API drug load is about 0.1 mg to about 2 grams or 10 mg to about 1.8grams or 500 milligrams to about 1.5 grams. In aspects, the API drugload is about 600 milligrams to about 1.5 grams. The amount of API maydepend on a variety of factors such as the need for additionalexcipients and the size of tablet. In aspects, the amount of API in theGRDF is a therapeutically effective amount for treating a particulardisease or condition over a prescribed time period, e.g., hourly (q1 h),q2 h-q8 h, b.d.s., and o.d.

In any of the aspects described herein, the body may include at leasttwo arms.

In any of the aspects described herein, the at least two arms may bepivotably connected to one another about a hinge assembly.

In any of the aspects described herein, at least one of the at least twoarms comprises a cavity defined therein configured to receive at least afirst portion of the API or diagnostic. In aspects, the cavity includesa volume ranging from about 100 mm³ to about 2000 mm³ or from about 200mm³ to about 1800 mm³. In aspects, the volume of the body may range fromabout 500 mm³ to about 1500 mm³. In embodiments, the volume of the bodymay range from about 800 mm³ to about 1200 mm³. In aspects, the volumeof the body may be about 950 mm³. In aspects, the at least one arm thatincludes the cavity includes an opening defined therein which may be incommunication with the gastric environment. This hole would be distallylocated from the hinge assembly.

In any of the aspects described herein, at least one of the at least twoarms may be configured to releasably engage the API or diagnostic. Inany of the aspects described herein, the API or diagnostic is positionedwithin a cavity defined in the body. In any of the aspects describedherein, the API may be positioned within the cavity in the form of acomposition. In any of the aspects described herein the API positionedin the cavity is released at a controlled rate over more than 6 hours,in aspects, over more than 8 hours, in aspects, over more than 10 hours.

In aspects according to the present disclosure, the body may include twoarms.

In any of the aspects described herein, the body comprising the at leastone arm, hinge and cavity may be is produced by for example, usinginjection molding, 3D printing, etc. In any of the aspects describedherein, the body injection molding or 3D printing. In any of the aspectsdescribed herein, the biasing element, the at least one of the at leasttwo arms, and hinge assembly is manufactured from pharmaceuticallyacceptable excipients as listed in IIG guidelines.

In any of the aspects described herein, the body is maintained in thecollapsed configuration by a retention mechanism and the body istransitioned to the expanded configuration by a hinge assembly. Itshould be understood that any retention method or mechanism that isconfigured to maintain the collapsed configuration of the GRDF prior toswallowing is envisioned. Several different aspects have been describedherein and include a capsule that erodes or dissolves upon contact withgastric fluid. In another aspects, in a case where the natural state ofthe GRDF is open (natural or biased configuration of one of the hingeassemblies described herein is open to expand the GRDF), there may be amaterial holding the GRDF closed which dissolves or erodes in thepresence of gastric fluid thereby releasing the GRDF to an expandedconfiguration. In other aspects, the material may be in the shape of anerodible band which encompasses the arms to maintain the GRDF in acollapsed configuration until the band erodes allowing expansion of theGRDF. Still other aspects include a glue-like material that keeps thetwo arms together until the glue-like material erodes allowing expansionof the GRDF. In another aspect, the retention mechanism may be a capsulewhich maintains the closed state and dissolves when introduced to afluid environment. may be the capsule itself.

In any of the aspects described herein, the oral pharmaceutical furthercomprises a capsule configured to encompass the body when disposed inthe collapsed configuration, the capsule configured to at leastpartially dissolve upon introduction to fluid to expose and release thebody from the collapsed configuration.

In any of the aspects described herein, the GRDF maintains a shelf lifedurability or shelf life stability for more than 2 years underaccelerated conditions.

In any of the aspects described herein, each arm may include a cavitydefined therein configured to receive an API or diagnostic.

In any of the aspects described herein, the at least two arms aremovable or pivotable about a hinge assembly.

In aspects, the at least two arms and the hinge assembly are releasableengaged to one another.

In any of the aspects described herein, the at least two arms detachfrom the hinge assembly at the predetermined period of time.

In any of the aspects described herein, the at least two arms detachfrom the hinge assembly when the API or diagnostic has beensubstantially released.

In any of the aspects described herein, the at least two arms include afirst arm comprising a first API or diagnostic and a second armcomprising a second API or diagnostic. In aspects, the second API ordiagnostic is incompatible with the first API or diagnostic.

In any of the aspects described herein, the at least two arms of thebody are configured to disengage from one another upon partial releaseof the API. In any of the aspects described herein, the predeterminedtime period is at least 4 hours, in aspects, at least 6 hours, inaspects, at least 8 hours, in aspects, at least 10 hours, in aspects, atleast 12 hours, in aspects, at least 18 hours. In any of the aspectsdescribed herein, the predetermined time period is in mammals such asdog or pig and preferably human.

In any of the aspects described herein, the size of each of individualarms and hinge is substantially maintained during transition betweenconfigurations. In aspects, there is less than 10%, in aspects, lessthan 5% change in size of each of the parts which make up the body,i.e., the hinge, arms etc. In aspects, this is so after exposure to 24hrs simulated gastric conditions. In any of the aspects describedherein, the size of at least one of the at least two arms issubstantially maintained during transition between the first and secondand then the second and third configurations.

In any of the aspects described herein, the hinge assembly may be madefrom one or more pharmaceutically acceptable ingredients. In any of theaspects described herein, the hinge assembly can include twointerconnected hinge portions that are pivotably coupled to each other,each hinge portion being connected to one of the at least two arms. Inaspects, each hinge portion is connected to one of the at least two armsby a mechanically engaging component such as the inner wall of thecavity in the arm. In aspects, the hinge assembly or portions areconfigured to rotate with respect to each other within a limited rangeof motion that is less than or equal to 90 degrees. In any of theaspects described herein, the hinge assembly is a unitary component.

In any of the aspects described herein, after the predetermined timeperiod has lapsed, the hinge assembly is configured to disengage fromthe at least two arms for release from the stomach. In any of theaspects described herein, the hinge assembly can disengage from the atleast two arms once the API is substantially released or the APIcomposition is substantially eroded. Substantially released or erodedmay be more than 70%, more than 75% or more than 80%. In aspects, thehinge assemblies or other connection mechanisms composed of one or morebase-sensitive materials can begin to disintegrate or erode once exposedto the proximal end of the arm's internal matrix (the API release systemor API composition) which includes basic material. In other aspects, thehinge assemblies or other connection mechanisms composed of one or moretime sensitive polymers can begin to disintegrate at a certain point intime. In yet other aspects, the hinge assemblies or other connectionmechanisms are connected to the arms in a certain mechanical fashion,with a certain mechanical shape or by one or more mechanical featuressuch that once the arms, insert tablet or hinge assembly erode via theintroduction of gastric fluids, the mechanical integrity of the hingeassembly or arms (or parts thereof) is compromised due to a change ofshape of one or more mechanical elements and, as a result, themechanical engagement is lost.

In any of the aspects described herein, the hinge assembly may beenvironment-sensitive, for example pH sensitive or preferably basesensitive, and is configured to deteriorate prior to expiration of thepredetermined period of time once the hinge assembly is exposed to abasic solution.

In any of the aspects described herein, at least a portion of the hingeassembly is manufactured using injection molded materials.

In aspects, the partial degradation of at least one of the at least twoarms or hinge assembly or partial release the API or diagnostic may bedue to a pH dependent polymer. In any of the aspects described herein,the pH dependent polymer may be configured to erode in a basicenvironment. In another aspect, a method is provided for ending gastricretention of the GRDF by inducing a change in a basic environment. Inany of the aspects described herein, as long as the hinge assemblyengagement with the arms is environment sensitive, and the environmentchanges or can be induced to change, one can induce an end to gastricretention. In aspects, the pH dependent polymer may be coating orinvolved in physical make up of an arm or hinge assembly.

In any of the aspects described herein, the body is produced byinjection molding or 3D printing.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) for extended retention in a stomach is provided andincludes: a body including a hinge assembly, the body configured to movebetween a collapsed configuration for ingestion to an expandedconfiguration for retention in the stomach; and at least one insertretained within a portion of the body and comprising an activepharmaceutical ingredient (API) and an excipient, wherein a ratio of theAPI to a total load of the both the API and the excipient is from about0.5 to about 0.95.

In any of the aspects described herein, the insert includes excipientsfor immediate release. According to another aspect of the disclosure,the ratio of the weight of the active pharmaceutical ingredients to theweight of the total weight of the insert tablet in the insert is fromabout 0.1 to about 0.99, in aspects, from about 0.5 to about 0.95, andin other aspects, from about 0.7 to about 0.9.

According to an aspect of the present disclosure, a pharmaceuticalformulation suitable for retention in the stomach is provided andincludes: a cellulose ester and a plasticizer combined in a ratioranging from about 3:1 to about 8:1, wherein the pharmaceuticalformulation is retained in the stomach for a time period of more than 4hours.

In any of the aspects described herein, the pharmaceutical formulationis retained in the stomach for a time period of more than 6 hours, inaspects, for a time period of more than 8 hours, in aspects, for a timeperiod of more than 12 hours, in aspects, for a time period of more than18 hours, in aspects, for a time period of more than 24 hours, inaspects, for a time period of more than 36 hours. In any aspect, theperiod of time is under fasted conditions or after a light meal.

In any of the aspects described herein, the GRDF is folded andpositioned in a capsule. In any of the aspects described herein theformulation further comprises retention arms or a hinge assembly.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a pharmaceuticallyacceptable material folded inside a capsule, wherein the pharmaceuticalacceptable material unfolds into a size suitable for gastric retentionin a time period of less than 5 minutes. In aspects, the time period forunfolding of the pharmaceutically acceptable material into a sizesuitable for gastric retention is less than 4 minutes, in aspects, lessthan 3 minutes, in aspects, less than 2 minutes.

In any of the aspects described herein, the GRDF further comprises anactive pharmaceutical ingredient.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a pharmaceuticallyacceptable material folded inside a capsule and including an activepharmaceutical ingredient, wherein an end to gastric retention of thedosage form is controlled by a release of the active pharmaceuticalingredient.

In any of the aspects described herein, the end to gastric retentionoccurs when more than 70% of the active pharmaceutical ingredient isreleased, in aspects, when more than 75% of the active pharmaceuticalingredient is released, in aspects, when more than 80% of the activepharmaceutical ingredient is released, in aspects, when more than 85% ofthe active pharmaceutical ingredient is released, in aspects, when morethan 90% of the active pharmaceutical ingredient is released, inaspects, when more than 95% of the active pharmaceutical ingredient isreleased, in aspects, when 100% of the active pharmaceutical ingredientis released.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a body including two armstransitionable between a collapsed configuration and an expandedconfiguration for retaining the GRDF within the stomach for apredetermined time period; and an active pharmaceutical ingredient (API)or diagnostic at least partially positioned within the body.

In any of the aspects described herein, a biasing element is configuredto maintain the two arms apart once the two arms transition to theexpanded configuration. In aspects, the biasing element is configured totransition the two arms from the collapsed configuration.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes a body including two armstransitionable from a first configuration swallowable by a user, asecond configuration for retaining the GRDF within the stomach for apredetermined period of time, and a third configuration wherein the twoarms disassemble after the elapse of the predetermined period of time.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: at least two armspivotably connected together and transitionable between a collapsedconfiguration wherein the at least two arms are disposed in closeproximity relative to one another and the GRDF is suitable forswallowing and an expanded configuration wherein the at least two armsare further apart from one another; an active pharmaceutical ingredient(API) or diagnostic at least partially contained within a cavity definedin at least one of the at least two arms; and a biasing elementconfigured to maintain the at least two arms apart once the at least twoarms transition to the expanded configuration.

In any of the aspects described herein, the at least two arms arepivotable about a hinge assembly. In aspects described herein, thebiasing element forms part of the hinge assembly. In aspects, the atleast two arms and the hinge assembly are releasable engaged to oneanother.

In any of the aspects described herein, the hinge assembly is a unitarycomponent.

In any of the aspects described herein, the hinge assembly includes twointerconnected hinge portions that are pivotably coupled to each other,each hinge portion being connected to one of the at least two arms. Inaspects, each hinge portion is connected to one of the at least two armsby a mechanically engaging component. In aspects, the hinge portions areconfigured to rotate with respect to each other within a limited rangeof motion that is less than or equal to 90 degrees.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a body including at leasttwo arms each having a predetermined length and configured to movebetween a collapsed configuration for ingestion to an expandedconfiguration for retention in the stomach; and an active pharmaceuticalingredient positioned within at least one of the two arms, wherein thepredetermined length of the at least one arm including the activepharmaceutical ingredient remains substantially the same during therelease of the active pharmaceutical ingredient.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a body including at leasttwo arms each having a predetermined length and configured to movebetween a collapsed configuration for ingestion to an expandedconfiguration for retention in the stomach; and an active pharmaceuticalingredient positioned within at least one of the two arms, wherein thepredetermined length of at least one of the two arms remainssubstantially the same following disassembly of the body.

According to an aspect of the present disclosure, an oral pharmaceuticalfor extended retention in a stomach is provided that includes: a bodyconfigured to transform about a hinge assembly between a collapsedconfiguration for ingestion and an expanded configuration for retentionwithin the stomach for a predetermined time period; and an activepharmaceutical ingredient (API) or diagnostic at least partiallypositioned within the body.

In any of the aspects described herein, another portion of the API ordiagnostic is concealed by the at least one arm of the body.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a body comprising a pHsensitive material and including at least two arms configured totransform from a collapsed configuration for ingestion to an expandedconfiguration for retention in the stomach, wherein the pH sensitivematerial is configured to force the disassembly of the body.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) for extended retention in a stomach is provided thatincludes: a body configured to transform between a collapsedconfiguration for ingestion and an expanded configuration for retentionwithin the stomach for a predetermined time period; and an activepharmaceutical ingredient (API) or diagnostic configured to releasablyengage the body, wherein the body is configured to disassemble uponpartial disintegration of the API, and wherein the body is made from apharmaceutically acceptable material wherein the size, shape anddurability of the body is substantially maintained while in the stomachfor the predetermined period of time.

In any of the aspects described herein the API is released at acontrolled rate over more than 6 hours, in aspects, over more than 8hours, in aspects, over more than 10 hours.

In any of the aspects described herein, the API or diagnostic is encasedby at least one of the at least two arms.

In any of the aspects described herein, the API or diagnostic isreleased via an opening defined within at least one of the two arms.

In any of the aspects described herein, the API or diagnostic is aninsert shaped to fit within a cavity defined in at least one of the atleast two arms.

In any of the aspects described herein, the insert includes excipientsfor immediate release.

In any of the aspects described herein, in the expanded configuration,the at least two arms define an interior angle of less than about 90°therebetween.

In any of the aspects described herein, the hinge assembly is pHsensitive and is configured to deteriorate prior to expiration of thepredetermined period of time once the hinge assembly is exposed to abasic solution.

In any of the aspects described herein, in the expanded configuration,the at least two arms define an interior angle between about 45 degreesand about 90 degrees, in aspects, the at least two arms define aninterior angle between about 45 degrees and about 80 degrees.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a body including at leasttwo arms, the body configured to transform between a collapsedconfiguration for ingestion and an expanded configuration for retentionwithin the stomach for a predetermined time period, wherein thegastroretentive dosage form maintains a mechanical strength anddimensions such that:

-   -   a. after 12 hr exposure to simulated gastric fluids [Rotating        apparatus having 37° C., pH2+Xanthan gum 0.125 gr/L, 25 RPM        mixing]—less than 5%, preferably less than 3% decrease in size        when placed in a compression modulus with repeated force applied        in the direction of refolding of 150 g/mm, up to 750 g    -   b. after more than 8 hr exposure to simulated gastric fluids        [Rotating apparatus having 37° C., pH2 Xanthan gum 0.125 gr/L,        25 RPM mixing]—size maintained to prevent passage through the 18        mm pipe test under 600 gr/F    -   c. after more than 24 hrs in a pig stomach—size maintained    -   d. after more than 24 hrs in a beagle dog stomach, 50% of the        GRDFs maintained size    -   e. after 24 hr exposure to simulated gastric fluids—less than        10% preferably less than 5% change in weight, length and        thickness of body.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a hinged body configuredto transform between a collapsed configuration for ingestion and anexpanded configuration for retention within the stomach for apredetermined time period, wherein the gastroretentive dosage formmaintains a mechanical strength and dimensions such that.

-   -   a. after 12 hr exposure to simulated gastric fluids [Rotating        apparatus having 37° C., pH2+Xanthan gum 0.125 gr/L, 25 RPM        mixing]—less than 5%, preferably less than 3% decrease in size        when placed in a compression modulus with repeated force applied        in the direction of refolding of 150 g/mm, up to 750 g    -   b. after more than 8 hr exposure to simulated gastric fluids        [Rotating apparatus having 37° C., pH2 Xanthan gum 0.125 gr/L,        25 RPM mixing]—size maintained to prevent passage through the 18        mm pipe test under 600 gr/F    -   c. after more than 24 hrs in a pig stomach—size maintained    -   d. after more than 24 hrs in a beagle dog stomach, 50% of the        GRDFs maintained size    -   e. after 24 hr exposure to simulated gastric fluids—less than        10% preferably less than 5% change in weight, length and        thickness of body.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) for extended retention in a stomach is provided thatincludes: a non-biodegradable body including a first arm and a secondarm configured to move between a collapsed configuration for ingestionto an expanded configuration for retention in the stomach, thenon-biodegradable body comprising a mixture including a pharmaceuticallyacceptable material and a plasticizer in a ratio ranging from about 3:1to about 12:1.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) for extended retention in a stomach is provided thatincludes: a body configured to transform between a collapsedconfiguration for ingestion and an expanded configuration for retentionwithin the stomach for a predetermined time period, wherein the GRDFexhibits gastric retention for more than 24 hrs under fasted conditionsin about 50% beagle dog.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a body configured totransform between a collapsed configuration for ingestion and anexpanded configuration for retention within the stomach for apredetermined time period, wherein the GRDF does not pass the 18 mm pipetest under 300 grForce after exposure to simulated gastric conditionsfor 24 hrs.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a body made of apharmaceutically acceptable material and including an API having a sizeand strength maintained after more than 85% API is release, such that itcannot pass the 18 mm pipe test under 300 grForce.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a body configured totransform between a collapsed configuration for ingestion and anexpanded configuration for retention within the stomach for apredetermined time period, wherein the GRDF does not pass the leafdurability test under 1250 grForce and exposure to simulated gastricconditions for 12 hrs.

According to an aspect of the present disclosure, a gastroretentivedosage form (GRDF) is provided that includes: a body configured totransform between a collapsed configuration for ingestion and anexpanded configuration for retention within the stomach for apredetermined time period, wherein the body displays less than 6%deformation when compressed by 350 grF after exposure to simulatedgastric conditions for 12 hrs.

In any of the aspects described herein, the GRDF further comprises anactive pharmaceutical ingredient. In any of the aspects describedherein, the GRDFs described herein may include a body which includes avolume ranging from about 100 mm³ to about 2000 mm³. In aspects, thevolume of the body may range from about 200 mm³ to about 1800 mm³. Inaspects, the volume of the body may range from about 500 mm³ to about1500 mm³. In embodiments, the volume of the body may range from about800 mm³ to about 1200 mm³. In aspects, the volume of the body may beabout 950 mm3. In any of the aspects described herein, the GRDF isfolded and positioned in a capsule.

In any of the aspects described herein, any of the GRDFs described orenvisioned herein may include an emergency release feature that allowsthe GRDF to pass through the pyloric valve for immediate removal fromthe stomach and gastrointestinal tract, if needed or causes immediatedisassembly outside of the gastric environment. Either in the presenceor upon exposure to an antidote or environment different than typicalgastric, the GRDF is configured to disassemble for passage from thestomach prior to expiration of the predetermined period of time ordisassemble if it has passed the gastric environment. An antidote orother triggering mechanism may be employed to initiate the emergencyrelease of the GRDF. In aspects, the GRDF includes a hinge assembly (orany other portion thereof) that is pH sensitive (for example sensitiveto a pH 5-5.5) such that under normal gastric conditions the hingeassembly (or any portion thereof) remains intact and the GRDF functionsas intended. However, if needed, the environmental pH can be slightlyincreased (to within the above pH sensitive range or any other specifiedrange) causing the mechanical integrity of the hinge assembly (or anyportion thereof) to erode causing the hinge assembly to disassemble fromone or both arms and pass through the pyloric valve for subsequentevacuation. For example, in aspects, the erosion may cause reducedmechanical pressure between the insert and the hinge assembly (or aportion thereof) to eventually release the hinge assembly from one orboth arm(s) and pass from the stomach.

In any of the aspects described herein, the pH-sensitive materialsmaking up only part of the GRDF for the emergency release may includematerials which dissolve, erode, and/or degrade at a pH higher than 5,and more particularly from a pH which ranges from about 5 to 7.5. Somenon-limiting examples of suitable pH-sensitive materials includepolyacrylamides, phthalate derivatives (i.e., compounds with covalentlyattached phthalate moieties) such as acid phthalates of carbohydrates,amylose acetate phthalate, cellulose acetate phthalate, other celluloseester phthalates, cellulose ether phthalates, hydroxypropyl cellulosephthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, methyl cellulose phthalate, polyvinyl acetatephthalate, polyvinyl acetate hydrogen phthalate, sodium celluloseacetate phthalate, starch acid phthalate, styrene-maleic acid dibutylphthalate copolymer, styrene-maleic acid polyvinyl acetate phthalatecopolymer, styrene and maleic acid copolymers, formalized gelatin,gluten, shellac, salol, keratin, keratin sandarac-tofu, ammoniatedshellac, benzophenyl salicylate, cellulose acetate trimellitate,cellulose acetate blended with shellac, hydroxypropylmethyl celluloseacetate succinate, oxidized cellulose, polyacrylic acid derivatives suchas acrylic acid and acrylic ester copolymers, methacrylic acid andesters thereof, vinyl acetate and crotonic acid copolymers.

In any of the aspects described herein, the body or the GRDF includingany of the components of the GRDF, i.e., the body, arms, hinge assembly,etc., is made from at least one pharmaceutically acceptable material andpreferably it is comprised of only pharmaceutically acceptable material,for example based on FDA's IIG list. In any of the aspects describedherein, the formulation may be non-biodegradable or biodegradable orparticularly suitable for the injection molding process. The choice ofpharmaceutically acceptable materials for GRDFs includes all materialsthat will maintain stability in the gastric environment and provideenough rigidity to prevent disassembly or disintegration prior to thedesired time (preferably through fasted and fed states). Any acceptablepharmaceutically approved polymeric materials such as cellulose acetate,ethocel, eudragit, or hydroxypropyl cellulose acetate succinate, with orwithout addition of a plactisizer, can be used for preparation of theGRDF. If the desire is a non-biodegradable formulation, one may provide,for example, a cellulose ester with plasticizer. In any aspect describedherein, the materials are selected and processed in a way that willenable each of the components of the GRDF to operate according to itsdefined functionality (e.g., rigidity for the arms and hinge, elasticityof spring, and stability in dissolution, as defined above). Differentmaterials may be used in order to better balance between durability andsafety or eventual disintegration; pH independence and dependence, etc.For example, in aspects, the ratio of cellulose acetate (CA) toplasticiser may contribute to the durability, elasticity, reducedbrittleness, independence from pH changes and decreased erodability.

In any aspect described herein, the body is in a size, shape anddurability suitable for be maintained while in the stomach for thepredetermined time period. For example, the body may comprise: celluloseester, HPMC acetate succinate, ethocel, eudragit or a plasticizer. Thecellulose ester may be selected from the group consisting of celluloseacetate, cellulose triacetate, hydroxypropylmethylcellulose acetatesuccinate, cellulose proprionate, cellulose acetate proprionate,cellulose acetate butyrate, and combinations thereof. In aspects, thecellulose ester comprises cellulose acetate. In any of the aspectsdescribed herein, the cellulose ester and the plasticizer are combinedin a ratio ranging from about 3:1 to about 8:1. In aspects, thecellulose ester and the plasticizer are combined in a ratio ranging fromabout 4:1 to about 6:1, in aspects, the cellulose ester and theplasticizer are combined in a ratio of about 4:1. In aspects, thepolymer may be selected from a listing comprising any one or more of thefollowing: cellulose ester, HPMC acetate succinate, ethocel or eudragit.The plasticizer may be any one or more of the following: dibutylsebacate, triethyl citrate, polyethylene glycol, polyethylene glycolmonomethyl ether, acetyl tributyl citrate, triacetine, glycerin,sorbitol, sorbitan solutions, castor oil, diacetylated monoglycerides,triethyl citrate, tributyl citrate and combinations thereof. Morespecifically, the cellulose ester may be cellulose acetate (CA). Thecellulose acetate (CA) to plasticiser ratio may be from about 3:1 toabout 12:1, or in other aspects from about 3.5 to about 8:1 or inanother aspect from about 4:1 to about 6:1, or specifically 4:1.

In any of the aspects described herein, the body of GRDF comprises aplasticizer selected from the group consisting dibutyl sebacate,triethyl citrate, polyethylene glycol, polyethylene glycol monomethylether, acetyl tributyl citrate, triacetine, glycerin, sorbitol, sorbitansolutions, castor oil, diacetylated monoglycerides, triethyl citrate,tributyl citrate and combinations thereof. In any of the aspectsdescribed herein, the body may include more than about 50 mg of theplasticizer per unit dosage form, in aspects, more than about 100 mg ofthe plasticizer per unit dosage form, in aspects, more than about 150 mgof the plasticizer per unit dosage form, in aspects, more than about 180mg of the plasticizer per unit dosage form, in aspects, more than about190 mg of the plasticizer per unit dosage form.

In any of the aspects described herein, the body may include more thanabout 50 mg, or more than about 200 mg of the cellulose ester per unitdosage form. In aspects, the body includes more than about 400 mg of thecellulose ester per unit dosage form, in aspects, more than about 600 mgof the cellulose ester per unit dosage form, in aspects, more than about700 mg of the cellulose ester per unit dosage form, in aspects, morethan about 750 mg of the cellulose ester per unit dosage form.

In any of the aspects described herein, the pharmaceutically acceptablematerial is hydroxypropylmethylcellulose and the plasticizer is triethylcitrate. In any of the aspects described herein, the pharmaceuticallyacceptable material is hydroxypropylmethylcellulose and the plasticizeris polyethylene glycol. In any of the aspects described herein, thepharmaceutically acceptable material is ethylcellulose and theplasticizer is triethyl citrate. In any of the aspects described herein,the pharmaceutically acceptable material includes methacrylic acid andmethyl methacrylate and the plasticizer is triethyl citrate.

In any of the aspects described herein, the GRDF formulation orcontrolled release formulation comprises cellulose ester and triacetinand is capable of less than 10% preferably less than 5% change inweight, length and thickness after 24 hr exposure to simulated gastricfluids.

In any of the aspects described herein, the body includes an openingdefined therein configured to expose the API or diagnostic to gastricfluids in the stomach once the capsule at least partially dissolves.Thus, depending on the rate of API/diagnostic release or desired endpoint for gastric retention, the one or more openings may increase thesurface area for release and erosion of the API/diagnostic orcomposition thereof.

In any of the aspects described herein, the GRDF provides mechanicalstrength and is capable of resisting forces applied by the stomach underboth fed and fasted condition. The mechanical strength is sufficient toenable, upon expansion of the GRDF, the preservation of the expandedconfiguration to provide gastric retention. More specifically, there isprovided a GRDF with collapsed and expanded configurations which resistsmechanical gastric forces even for a period of time.

In any of the aspects, the GRDFs i.e., the body, arms, hinge assembly,etc., may provide a mechanical durability to remain intact, i.e.,assembled, over a period of time and is capable of resisting forcesapplied by the stomach under both fed and fasted condition. Themechanical strength is sufficient to enable, upon expansion of the GRDF,the preservation of the expanded configuration to provide gastricretention. More specifically, there is provided a GRDF (e.g., anon-biodegradable GRDF) with collapsed and expanded configurations whichresists mechanical gastric forces wherein the gastroretentive dosageform is adapted to or capable of maintaining mechanical strength anddimensions to endure any one or more of the following:

-   -   a. after 12 hr exposure to simulated gastric fluids [Rotating        apparatus having 37° C., pH2+Xanthan gum 0.125 gr/L, 25 RPM        mixing]—less than 5%, preferably less than 3% decrease in size        when placed in a compression modulus with repeated force applied        in the direction of refolding of 150 g/mm, up to 750 g    -   b. after more than 8 hr exposure to simulated gastric fluids        [Rotating apparatus having 37° C., pH2 Xanthan gum 0.125 gr/L,        25 RPM mixing]—size maintained to prevent passage through the 18        mm pipe test under 600 gr/F    -   c. after more than 24 hrs in a pig stomach—size maintained    -   d. after more than 24 hrs in a beagle dog stomach, 50% of the        GRDFs maintained size    -   e. after 24 hr exposure to simulated gastric fluids—less than        10% preferably less than 5% change in weight, length and        thickness of body.

In any of the aspects described herein, the body comprises a mechanicaldurability to remain intact over a period of time of at least 1 hour andunder a repeated force of at least 400 grF. In aspects, the time periodis at least 3 hours, in aspects, the time period is at least 6 hours, inaspects, the time period is at least 9 hours, in aspects, the timeperiod to remain intact is at least 24 hours. In any of the aspectsdescribed herein, the repeated force of at least 600 grF, in aspects,the repeated force ranges from about 400 to about 3000 grF.

In any of the aspects described herein, the pharmaceutical formulationmay be able to be retained in a human stomach for a time period of morethan 6 hours, in aspects, for a time period of more than 8 hours, inaspects, for a time period of more than 12 hours, in aspects, for a timeperiod of more than 18 hours, in aspects, for a time period of more than24 hours, in aspects, for a time period of more than 36 hours. In any ofthe aspects described herein the formulation further comprises retentionarms or a hinge assembly.

In any of the aspects described herein the formulation further comprisesretention arms or a hinge assembly.

In another aspect, a method is provided for ending gastric retention ofthe GRDF by inducing basic environment. As long as the hinge assemblyengagement with the arms is environment sensitive, and the environmentchanges or can be induced to change, one can induce an end to gastricretention. The pH dependent polymer may be coating or involved inphysical make up of an arm or hinge assembly.

In another aspect, GRDFs may be manufactured by a number of processesincluding injection molding 3D printing and the like, as will be clearto one skilled in the art, such as the manufacturing techniquesdescribed in WO 2003057197 or in Zema et. al., Journal of ControlledRelease, Volume 159 (2012) 324-331. For example, a mold can beconstructed in the desired shape of the GRDF and filled with appropriatematerial(s) in liquid state and then allowed to cure by chemicalprocesses or cooled if thermosetting material(s) are used. The GRDFsdescribed herein or any parts thereof, e.g., arms, hinge assembly,springs, etc. may be made from pharmaceutically acceptable materials oringredients, e.g., one or more ingredients listed in the IIG guidelines.In aspects, the GRDF may include a body which is made from at least onepharmaceutically acceptable material wherein the size, shape, anddurability of the body are maintained while in the stomach for apredetermined time period of gastric retention. The use of injectionmolding applied to the specified ingredients in the specified moldsresulted in less than 10% variation, in embodiments, less than 5%variation, in detail as small as 500 μm.

In any aspect, the GRDF may be configured for use with one or moreadditional APIs with different release profiles, e.g., an additional APIdesigned for immediate release. The additional API, (e.g., an APIdesigned for immediate release) may be located at the distal end of theinsert and used with a GRDF with an opening at a distal end of one orboth arms. In this instance, the configuration of the GRDF along withthe API being disposed at a distal end of the insert directs the initialinfusion of gastric fluids into the distal opening of the one or botharms and into immediate contact with the additional API promotingimmediate release. In aspects, additional API may be included as a layerencompassing the capsule or surrounding the GRDF, or a layerencompassing one or both arms (or portions thereof).

According to an aspect of the present disclosure, a method of assemblinga gastroretentive dosage form (GRDF) is provided and includes: insertingan insert tablet into a cavity of a body formed by injection molding;and combining the body with a hinge assembly.

According to an aspect of the present disclosure, a method of deliveryof an API or diagnostic is provided that includes administering to apatient a GRDF of any of the previous claims in a closed configuration.

According to an aspect of the present disclosure, a method ofmanufacturing a dosage form for gastric retention is provided thatincludes forming a body of the dosage form including a cellulose estercomposition.

In any aspect described herein, the cellulose ester composition includesa cellulose ester and a plasticizer. In aspects, the cellulose ester iscellulose acetate and the plasticizer is triacetin.

According to an aspect of the present disclosure, a method of forcing adisassembly of a GRDF within a patient is provided that includes:administering a GRDF to a patient; and administering an antidote to thepatient, wherein the antidote increases a pH of the patient's stomachforcing the GRDF to disassemble into pieces of sufficient size toevacuate the stomach.

In aspects, the GRDF includes a body comprising a pH sensitive materialwhich represents less than about 20% of a total weight of the body,wherein the pH sensitive material is configured to force the GRDF todisassemble.

According to an aspect of the present disclosure, use of an immediaterelease formulation in the manufacture of a GRDF is provided. In any ofthe aspects described herein, the formulation is an insert (tablet).

According to an aspect of the present disclosure, a controlled releaseformulation is provided that includes a body including a cavity suitablefor retaining an API composition, wherein the body defines a surfacearea of exposure of the API composition which allows for the controlledrelease of the API.

In any of the aspects described herein, the API is released over morethan 4 hours, in aspects, over more than 8 hours, in aspects, over morethan 12 hours, in aspects, over more than 18 hours, in aspects, overmore than 24 hours.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

Various aspects of the present disclosure are described herein withreference to the drawings wherein like reference numerals identifysimilar or identical elements:

FIG. 1 depicts a perspective view of an or& pharmaceutical orgastroretentive dosage form (GRDF) shown in an expanded configuration,according to a first exemplary embodiment of the present disclosure;

FIG. 2 depicts a side view of the GRDF of FIG. 1 with parts separated;

FIG. 3 depicts a cross-sectional view of the GRDF of FIG. 1 taken alongline 3-3 of FIG. 1;

FIG. 4 depicts a perspective view of a hinge of the GRDF of FIG. 1 in anopen configuration;

FIG. 5A depicts a perspective view of an insert of the GRDF of FIG. 1;

FIG. 5B depicts a perspective view of another embodiment of an insert ofthe GRDF of FIG. 1 including two active pharmaceutical ingredientsseparated by a non-active pharmaceutical ingredient;

FIG. 6 depicts a perspective view of a first biasing arm of the GRDF ofFIG. 1;

FIG. 7 depicts perspective view of a second arm of the GRDF of FIG. 1;

FIG. 8 depicts a perspective view of a GRDF shown in an expandedconfiguration, according to a second exemplary embodiment of the presentdisclosure;

FIG. 9 depicts a side view of the GRDF of FIG. 8 with parts separated;

FIG. 10 depicts a cross-sectional view of the GRDF of FIG. 8;

FIG. 11 depicts a perspective view of a hinge of the GRDF of FIG. 8 inan open configuration;

FIG. 12 depicts a perspective view of a second arm of the GRDF of FIG.8;

FIG. 13 depicts a perspective view of a GRDF shown in an expandedconfiguration, according to a third exemplary embodiment of the presentdisclosure;

FIG. 14 depicts a perspective view of a GRDF shown in an expandedconfiguration, according to a fourth exemplary embodiment of the presentdisclosure;

FIG. 15 depicts a cross-sectional view of the GRDF of FIG. 14;

FIG. 16 depicts the GRDF of FIG. 1 in a collapsed configuration andpositioned in one half of a delivery capsule, the other half of thedelivery capsule being omitted to better show the collapsed condition ofthe hinge;

FIGS. 17A-17C depict varying views of a GRDF shown in an expandedconfiguration, according to a fifth exemplary embodiment of the presentdisclosure;

FIG. 18 depicts a cross-sectional view of the GRDF of FIG. 17A takenalong line 18-18 of FIG. 17A;

FIG. 19 depicts a side, elevational view of the GRDF of FIG. 17A shownin a collapsed configuration;

FIG. 20 depicts a side, elevational view of the GRDF of FIG. 17A (or anyother disclosed GRDF) stored in a delivery capsule;

FIG. 21 depicts a perspective view of a first biasing arm of the GRDF ofFIG. 17A;

FIGS. 22A and 22B depict varying perspective views of the second arm ofthe GRDF of FIG. 17A;

FIGS. 23A through 23D depict varying perspective views of a hingeassembly of the GRDF of FIG. 17A;

FIGS. 24A and 24B depict varying perspective views of a dip portion ofthe hinge assembly of FIGS. 23A through 23D;

FIGS. 25A and 25B depict varying perspective views of a post portion ofthe hinge assembly of FIGS. 23A through 23D;

FIG. 26 depicts a perspective view of an insert of the GRDF of FIG. 17A;

FIG. 27 depicts a top, perspective view of a second arm sub-assembly ofthe GRDF of FIG. 17A;

FIG. 28 depicts a side, cross-sectional view of the second armsub-assembly of FIG. 27 taken along line 28-28 of FIG. 27;

FIG. 29 depicts an enlarged, cross sectional view of the second armsub-assembly of FIG. 27 taken along line 29-29 of FIG. 27;

FIG. 30 depicts a perspective view of a first biasing arm sub-assemblyof the GRDF of FIG. 17A;

FIG. 31 depicts a side, cross-sectional view of the first biasing armsub-assembly of FIG. 30 taken along line 31-31 of FIG. 30;

FIG. 32 depicts an enlarged, top perspective of the first biasing armsub-assembly of FIG. 30;

FIG. 33 depicts a side view of a GRDF according to another exemplaryembodiment of the present disclosure shown in a collapsed configuration;

FIGS. 34A and 34B depict varying views of the GRDF of GIF. 33 disposedin an expanded configuration;

FIG. 35 depicts a top view of one arm of the GRDF of FIG. 33 including aplurality of openings and engagement slots disposed therein;

FIGS. 36A and 36B depict varying views of a hinge assembly in anassembled configuration;

FIGS. 37-39 depict the results of various dissolution tests;

FIG. 40A depicts a schematic illustration of a pipe testing apparatus;

FIG. 40B depicts a schematic illustration of the GRDF in varyingorientations;

FIG. 41 depicts a schematic illustration of a spring durability testingapparatus;

FIGS. 42 and 43 depict graphs showing the results of the springdurability test using the apparatus of FIG. 41;

FIGS. 44 and 45 are photographs of the extent of deformation of the GRDFof the Pig Study of Example 9;

FIG. 46 is a photograph of a GRDF having radio opaque threads (shown inblack) attached thereto;

FIG. 47 is a graphical illustration of the percentage of erosion overtime of the insert including the API;

FIGS. 48-51 are X-rays illustrating the gastric retention of the GRDFand the barium impregnated polyethylene spheres (BIPS) at 4 hr, 8 hr, 12hr, and 24 hr intervals, respectively;

FIG. 52 is a graphical illustration of the dissolution profile anddisassembly time of the GRDF with varying hole geometries;

FIG. 53A-53D depict schematic illustrations of an ingestion throughdisassembly cycle of any one of the GRDFs of the present disclosure; and

FIG. 54 depicts an insert prepared with specific dimensions according toone embodiment of the present disclosure for use with some of theExamples disclosed herein.

DETAILED DESCRIPTION

AH of the patent references and journals that are referenced herein areincorporated by reference herein in their entirety and for all purposes.

The wording hereinbelow is implied in the common meaning of thedefinitions and statements as known to those skilled in the art.However, there are several terms that should be understood in theconcept of the present disclosure as follows:

“Gastroretentive dosage form(s)” (GRDF or GRDFs in the plural) refers todosage forms which reside in the confines of the stomach for the purposeof providing a platform for the controlled release of biologicallyactive agents or diagnostic formulations. The GRDF is also referred toherein as an oral pharmaceutical, as well as a dosage form for extendedretention in a stomach.

“Gastric retention” is the maintenance or holding of a pharmaceutical inthe stomach, for a time period longer than the time it would have beenretained in the stomach when delivered in a free form or within agastro-intestinal (GI) delivery vehicle which is not consideredgastroretentive. Gastro-retentivity may be characterized by retention inthe stomach for a period that is longer than the normal emptying timefrom the stomach, such as longer than about 2 hours, in some caseslonger than about 3 hours, and in many cases more than about 4, 6, 8 or10 hours. Gastro-retentivity typically means retention in the stomachfor a period of time of about 3, 4, 6, 8, 10, or at times 18 hours, evenup to about 21 hours or longer. Gastro-retentivity may also meanretention in the stomach for a predetermined time period of at least 4,6, 8, 10, 12, and 18 hours.

As used herein, a size “suitable for swallowing” is any size and/orshape of a pharmaceutical unit that is capable of being swallowed byeither a human or an animal.

As used herein, a “body” is meant to include any collection of parts ormaterials that are more or less constrained or otherwise connected tomove together by translation or rotation.

As used herein, “excipient” refers to a component, or mixture ofcomponents, that is used in the formulation of the compositions orinserts of the present disclosure to give desirable characteristics tothe composition or insert. As used herein, the term “pharmaceuticallyacceptable” refers to those compounds, materials, compositions,compacts, salts, and/or dosage forms which are, within the scope ofsound medical judgment, suitable for contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problematic complications over the desired durationof treatment commensurate with a reasonable benefit/risk ratio. In someembodiments, the term “pharmaceutically acceptable” means approved by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopeia or other generally recognized internationalpharmacopeia for use in animals, and more particularly in humans.Various pharmaceutically acceptable excipients can be used. In someembodiments, the pharmaceutically acceptable excipient can be, but isnot limited to, an alkaline agent, a stabilizer, an adhesion agent, aseparating agent, a coating agent, an exterior phase component, acontrolled-release component, a solvent, a surfactant, a humectant, abuffering agent, a filler, an emollient, or combinations thereof.Excipients in addition to those discussed herein can include excipientslisted in, though not limited to, Remington: The Science and Practice ofPharmacy, 21st ed. (2005). Inclusion of an excipient in a particularclassification herein (e.g., “solvent”) is intended to illustrate ratherthan limit the role of the excipient. A particular excipient can fallwithin multiple classifications.

As used herein, an “oral pharmaceutical” is anything administered orallywhose components are made up of pharmaceutically acceptable materials.

As used herein, diagnostic or an active pharmaceutical ingredient (API)is meant to include any substance relevant for gastric retention asrecognized in the art. A wide variety of APIs (which may be therapeutic,diagnostic or otherwise beneficial) may be employed in accordance withthe aspects of the present disclosure. Any API which is relevant forgastric retentive delivery or as a diagnostic known in the arts isintended to be encompassed herein. Relevant APIs are not limited to, butmay include the following: APIs acting locally in the stomach; APIsprimarily absorbed in the stomach; APIs poorly soluble in alkaline pH;APIs with narrow windows of absorption; APIs absorbed rapidly from theGI tract; APIs that degrade in the colon; and APIs that disturb colonicmicrobes.

Active pharmaceutical ingredients (APIs) may include but are not limitedto the following: prochlorperazine edisylate, ferrous sulfate,albuterol, aminocaproic acid, mecamylamine hydrochloride, procainamidehydrochloride, amphetamine sulfate, methamphetamine hydrochloride,benzphetamine hydrochloride, isoproterenol sulfate, phenmetrazinehydrochloride, bethanechol chloride, methacholine chloride, pilocarpinehydrochloride, atropine sulfate, scopolamine bromide, isopropamideiodide, tridihexethyl chloride, phenformin hydrochloride, metformin,methylphenidate hydrochloride, theophylline cholinate, cephalexinhydrochloride, diphenidol, meclizine hydrochloride, prochlorperazinemaleate, phenoxybenzamine, thiethylperazine maleate, anisindione,diphenadione erythrityl tetranitrate, digoxin, isoflurophate,acetazolamide, nifedipine, methazolamide, bendroflumethiazide,chlorpropamide, glipizide, glyburide, gliclazide, tobutamide,chlorproamide, tolazamide, acetohexamide, troglitazone, orlistat,bupropion, nefazodone, tolazamide, chlormadinone acetate, phenaglycodol,allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole,hydrocortisone, hydrocorticosterone acetate, cortisone acetate,dexamethasone and its derivatives such as betamethasone, triamcinolone,methyltestosterone, 17-β-estradiol, ethinyl estradiol, ethinyl estradiol3-methyl ether, prednisolone, 17-β-hydroxyprogesterone acetate,19-nor-progesterone, norgestrel, norethindrone, norethisterone,norethiederone, progesterone, norgesterone, norethynodrel, terfandine,fexofenadine, aspirin, acetaminophen, indomethacin, naproxen,fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate,propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine,imipramine, levodopa, selegiline, chlorpromazine, methyldopa,dihydroxyphenylalanine, calcium gluconate, ketoprofen, ibuprofen,cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate,vincamine, phenoxybenzamine, diltiazem, milrinone, captropril, mandol,quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen,fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuninal,nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine,lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine, lisinopril,enalapril, captopril, ramipril, enalaprilat, famotidine, nizatidine,sucralfate, etintidine, tetratolol, minoxidil, chlordiazepoxide,diazepam, amitriptyline, and imipramine, and pharmaceutical salts ofthese active agents. Further examples are proteins and peptides whichinclude, but are not limited to, cyclosporins such as cyclosporine A,insulin, coichicine, glucagon, thyroid stimulating hormone, parathyroidand pituitary hormones, calcitonin, renin, prolactin, corticotrophin,thyrotropic hormone, follicle stimulating hormone, chorionicgonadotropin, gonadotropin releasing hormone, bovine somatotropin,porcine somatropin, oxytocin, vasopressin, prolactin, somatostatin,lypressin, pancreozymin, luteinizing hormone, LHRH, interferons,interleukins, growth hormones such as human growth hormone, bovinegrowth hormone and porcine growth hormone, fertility inhibitors such asthe prostaglandins, fertility promoters, growth factors, and humanpancreas hormone releasing factor.

As used herein, the term “arm” or “arms” includes any structure thatincludes a length, width and thickness and aids in achieving size forgastric retention. An arm as described herein may retain an activepharmaceutical or diagnostic. It may define a cavity therein configuredto retain an insert or pharmaceutical tablet (made from one or moreAPIs, diagnostics, excipients and/or polymers). An arm as describedherein may be made from API, diagnostics, polymers, excipients, etc.

As used herein, the term “hinge assembly” includes any mechanism adaptedto permit relative movement between two or more structures, e.g., arms.The hinge assembly may consist of one integral part (e.g., a livinghinge) or one or more parts that are assembled in the conventionalsense. The hinge assembly may be durable in the stomach for a period oftime, and it may attach to one or more arms in both the collapsed andexpanded configurations. The hinge assembly may be capable of, at apredetermined time or upon occurrence of a mechanical event, disengagingfrom the one or more arms.

As used herein, the term “mechanical event” includes any event thatchanges the physical properties of one or more structures over time orupon contact with another material or fluid, e.g., gastric fluid insidethe body. Absorption, dissolution, melting, degradation, erosion, pHchange or temperature change, etc. are all examples of mechanicalevents.

As used herein an “erodible” material includes any material thatdegrades upon introduction to a specified environment or upon contactwith a specified material or fluid, e.g., a gastric environment orgastric fluid.

As used herein, the term “collapsed configuration” of the GRDF is thatstate prior to ingestion where the GRDF is a size suitable forswallowing.

As used herein, the term “expanded configuration” of the GRDF is thatstate after ingestion which is capable of maintaining the GRDF in thestomach (gastric retention) and preventing passage through the pyloricvalve.

As used herein, the term “upon exposure to gastric fluid” or undersimulated gastric conditions is meant to be taken literally or whenneeded, based on a suitable model. One example of such a suitable modelincludes exposure to 400 ml of 0.1N HCl and 150 gram glass beads in a500 mL dissolution chamber, at 37° C. at 8 RPM. In another model,Xanthan gum 0.125 gr/L, pH2 is at 37° C.

As used herein, the term “pharmaceutically acceptable” refers to amaterial that is not biologically or otherwise unacceptable when used inthe invention. For example, the term “pharmaceutically acceptablecarrier” refers to a material that can be incorporated into acomposition and administered to a patient without causing unacceptablebiological effects or interacting in an unacceptable manner with othercomponents of the composition. Such pharmaceutically acceptablematerials typically have met the required standards of toxicological andmanufacturing testing, and include those materials identified assuitable inactive ingredients by the U.S. Food and Drug Administration.

The present disclosure provides a GRDF and a method of use thereof. TheGRDF is swallowed in a collapsed configuration, expands in the stomach,performs its intended function for a predetermined time period, and atthe end of the time period or upon occurrence of a mechanical event,disassembles and/or disintegrates for eventual passage through thepyloric valve of the stomach. After exiting the stomach, the GRDF safelypasses through the rest of the gastrointestinal system and/or is simplyabsorbed by the body. In embodiments, the GRDF is configured todisintegrate completely. In other embodiments, the GRDF is configured toonly disintegrate to an extent necessary for evacuation. In yet otherembodiments, parts of the GRDF do not disintegrate and are evacuatedintact for later retrieval, e.g., for diagnostic purposes or when theGRDF houses a diagnostic device.

It should be understood that the gastric retention may be attained dueto the arms and/or hinge assembly, while the structure of the arms (withslight modifications of formulation of the insert depending on length oftime needed) provide for the controlled release of the API ordiagnostic.

Referring now specifically to one embodiment of a GRDF generallydesignated by reference numeral 10 shown in FIGS. 1-8 and 16, GRDF 10includes a body 5 having first and second arms 1 and 2, respectively,that are releasably connected to one another by a hinge assembly 4. Arms1 and 2 are capable of pivoting about hinge assembly 4 from a collapsedconfiguration, as shown in FIG. 16, to an expanded configuration, asshown in FIG. 1. In embodiments, the hinge assembly 4 is made frompharmaceutically acceptable materials or ingredients.

In the expanded configuration, the arms 1 and 2 may be oriented at aninternal angle β. In embodiments, angle β is more than 90 degrees. Inanother envisioned embodiment, the internal angle β between arms 1 and 2may be between about 45 degrees and about 90 degrees. In one embodiment,the internal angle between arms 1 and 2 may be between about 45 degreesto about 80 degrees. Each arm 1 and 2 includes a substantially hollowinner cavity 24 and 25, respectively, defined therein and configured toreceive an insert 3 that may include any combination of activepharmaceutical ingredients (APIs), diagnostic devices or materialsand/or various excipients and polymers. It should, of course, beunderstood that in embodiments only one of arm 1 or arm 2 is configuredto receive the insert 3.

As shown in FIG. 4, hinge assembly 4 includes a pair of opposing biasingelements 12 and 13 that are configured to mechanically engage arms 1 and2, respectively. Elements 12 and 13 are joined together by a livinghinge 15 which includes an elastically deformable portion 16 that biaseselements 12 and 13 (and, in turn, arms 1 and 2) into the expandedconfiguration (See FIGS. 3 and 4) once deployed as explained in moredetail below. Hinge assembly 4 may be unitary, as shown, or it mayinclude multiple components (e.g., components that separate after apredetermined period within the stomach or upon occurrence of amechanical event—See FIGS. 17-33).

As can be appreciated, hinge assembly 4 connects arms 1 and 2, however,any physical or mechanical mechanism(s) may be employed to connect arms1 and 2. For example, instead of hinge assembly 4, arms 1 and 2 may beconnected by a clip, clamp, snap, weld, adhesive, joint, dovetail,mating surface(s), tether, post, pin, slot, recess, fastener, fixture,mechanical thread, friction, or stitch for example. The connection ofthe arms 1 and 2 to the hinge assembly 4 may be accomplished byadhesive/chemical bonding such as a pharmaceutical binder whichfunctions as a glue, for example. Alternatively, the arm-to-hingeassembly interface may include any known mechanical engagement.

FIG. 5A shows a perspective view of the insert 3 which may be insertedinto respective cavities 24 and 25 defined within one or both arms 1 and2. As can be appreciated, insert 3 is structure that holds or containsthe API or diagnostic. Insert 3 may include any geometric shape and thecorresponding cavity, e.g., cavity 24 of arm 1, may include acomplementary geometric shape to receive the insert 3 in a manner thatallows mechanical separation of the arm, e.g., arm 1, after apredetermined time period or upon occurrence of a mechanical event asdescribed in more detail below. As shown, insert 3 includes an exposedsurface 120 and an engagement surface 110 separated by a ledge 115. Theexposed surface 120 is that portion of the insert 3 that contains theAPI or diagnostic and which is exposed to the gastric fluids asdescribed below. The engagement portion 110 and the ledge 115 cooperateto maintain engagement of the insert 3 with the hinge assembly 4 until asufficient portion of the engagement portion 110 or the ledge 115 erodesupon exposure to gastric fluids and the mechanical integrity of the GRDF10 fails causing disassembly. As can be appreciated, the engagementportion 110 and/or ledge 115 may be any geometric shape that togetherwith the geometric shape of the insert 3 maintain the GRDF 10 in anassembled configuration prior to erosion.

Each insert 3 may be formulated to include one or more activepharmaceutical ingredients (APIs), various diagnostic materials ordevices, or a variety of excipients and polymers depending upon aparticular purpose. The API is not limited to any particular class ofpharmaceutical. The diagnostic material or device may be a camera, asensor, a microchip, a radioactive tracer, a combination of one or morechemical strips or testing fixtures, micro genetic labs or arrays andthe like, e.g., commonly terms “lab-on-a-chip technologies”, etc. Thediagnostic may or may not be erodible. In embodiments, the diagnosticdevice may be retrievable or programmed to communicate with an outsidesource. In embodiments where it is desirous to maintain the integrity orpartial integrity of the diagnostic device (such as where the diagnosticis not erodible) then either arm 1 or 2 and/or the hinge assembly 4 maybe erodible to achieve disassembly of the GRDF 10.

As an alternative to the unitary insert 3 that is shown in FIG. 5A anddescribed herein, more than one API may also be separated into separateinserts or tablets, for example, when there are incompatible chemicalsthat cannot be readily combined into a single unitary insert 3 orformulation. In other embodiments, the insert 3 may be compartmentalizedor layered to control the rate of release of the API. For example, FIG.5B depicts a perspective view of another embodiment of insert 3′ thatincludes two APIs separated by a non-active pharmaceutical ingredient111. In this instance, the insert 3′ may include a portion containing anAPI which releases at a predetermined rate, followed by a portioncontaining no API (placebo or various excipients or polymers that erodeat a predetermined rate), followed by a portion that includes the sameor a different API. As can be appreciated, controlling the release ofAPI in this manner can mimic a particular dosing schedule for aparticular patient alleviating the need for the patient to take repeateddosages of a particular medicine at particular time periods. Moreover,depending upon the various polymers and excipients used or the shape ofthe insert 3 or 3′, the dosage period may be lengthened considerably.

For example, a person having to take a medicine three times per day maybe reduced to a once-per-day dosage. Someone having to take a medicineonce-per-day may be able to take a GRDF 10 once-per-week or longer anddeliver the same effective dosing. In this instance, the GRDF 10 isconfigured to facilitate erosion or dissolution of the insert 3 (whichreleases the API) in a predetermined manner or along a particularerosion pathway. It is important to note, the structure holding the APIor diagnostic in place, e.g., the insert which includes an APIcomposition including polymers and excipients, dissolves, disintegrates,erodes, etc. thereby releasing the API and/or exposing/releasing thediagnostic.

As explained in more detail below with reference to the configuration ofthe various openings and slots defined within the arms 1 and 2 of theGRDF 10, this may be accomplished by controlling or limiting theexposure of the insert 3 to certain areas along the arms 1 and 2, e.g.,controlling the amount of surface area of the insert 3 exposed togastric fluids along the GRDF 10. As can be appreciated, controlling therelease rate of the insert 3 in any of the fashions described herein mayextend the life of the insert 3 and enable one GRDF to effectivelyprovide the necessary API over an extended period of time while beingretained within the stomach.

With respect to embodiments where the insert 3 includes a diagnosticmaterial or device, after ingestion, the GRDF 10 expands for retentionwithin a subjects stomach for a predetermined period of time to completethe diagnostics. During this time, other portions of the GRDF 10 areexposed to gastric fluids which erode or dissolve one or more portionsof the GRDF 10 (e.g., hinge assembly 4 or hinge arms 12 and 13) over thepredetermined time or upon the occurrence of a mechanical event. Onceeroded, the GRDF 10 disassembles and moves through the pyloric valve andthrough the intestinal tract for subsequent retrieval.

FIG. 6 depicts a perspective view of the first arm 1 of the GRDF 10. Asnoted above, the interior of arm 1 includes a cavity 24 to accommodateinsert 3 that has a complementary shape to insert 3, e.g., asemi-cylindrical shape with a semi-spherical surface at a free end thereof that accommodates the corresponding semi-spherical surface of insert3. The inner facing surface of arm 1 includes an opening 17 definedtherein which is configured to expose a portion of insert 3 to gastricfluids. Alternatively or in addition to opening 17, another opening 21may be defined in the distal end of arm 1 (i.e., the end furthest fromhinge assembly 4) which is configured to expose the distal-most portionof the insert 3 to gastric fluids to encourage or promote adistal-to-proximal pathway of erosion of the insert (and release of theAPI or diagnostic) and eventual disassembly of the of GRDF 10. A varietyof slots 18 may also be defined within one or both arms 1 and 2 (SeeFIG. 8).

As explained in further detail below, promoting the release or erosionof the insert 3 in this fashion may facilitate mechanical disassembly ofthe GRDF 10 after the predetermined time period. In other words, theshape, size and location of opening 21 may influence the release timingor erosion of one or more components of the GRDF 10 which correlates tothe overall time the GRDF 10 is maintained within the stomach. As can beappreciated, additional openings and or slots of varying size and shapemay be defined within the arms 1 and 2 depending upon the length ofgastric retention of the GRDF 10 desired or the rate of erosion desiredof the insert 3 (See FIGS. 33 through 35). For example, in oneembodiment, distal opening 21 may be the only area of the GRDF 10 thatexposes the insert 3 to gastric fluids which, as mentioned above, maycreate a distal-to-proximal pathway of erosion of the insert 3. In thisinstance the insert 3 erodes proximally or along a proximal pathway (andrelease API in a controlled fashion) over a predetermined time untilenough of the insert 3 is eroded and the GRDF 10 loses mechanicalintegrity to hold its shape and disassembles for passage through thepyloric valve.

As shown in FIG. 6, a biasing element 9 may be integral with arm 1 andelastically deformable relative thereto. Biasing element 9 is configuredto bias arms 1 and 2 into the expanded configuration of the GRDF 10 asshown in FIG. 1. Once the GRDF 10 is expanded within the stomach,biasing element 9 also prevents arms 1 and 2 from returning to thecollapsed configuration that is shown in FIG. 16. Biasing element 9 maybe configured to engage a corresponding T-shaped slot 18 defined withinarm 2 to prevent the arms 1 and 2 from returning to the collapsedconfiguration. According to another embodiment, biasing element 9 may beomitted, and the hinge assembly 4 may be formed of a shape memorymaterial (SMM) such as polylactic acid or a shape memory alloy (SMA),e.g., Nitinol®, which is configured to prevent arms 1 and 2 fromreturning to the collapsed configuration. Other elements of the GRDF 10may also be formed of SMMs or SMAs as explained in more detail below.

FIG. 7 shows a perspective view of second arm 2 of the GRDF 10. Arm 2also includes a semi-cylindrical shape with a semi-spherical surface atone end. The interior of arm 2 also includes a cavity 25 defined thereinconfigured to accommodate a second insert 3 (e.g., a different insert 3than is contained within arm 1). Second insert 3 may include the sameAPIs as the insert in arm 1 or different APIs than the insert in arm 1or may include one or more diagnostics. The inner facing surface of arm2 includes a T-shaped slot 18 defined therein which is configured toexpose a portion of insert 3 to gastric fluids. Any number orconfiguration of slots 18 may be utilized in conjunction with any numberof openings (e.g., similar to opening 17 with respect to arm 1) orT-shaped slot 18 may be omitted or partially omitted depending upon aparticular purpose. A distal opening 19 may be defined at the distal endof arm 2 (furthest from hinge assembly 4). Similar to the opening 21described above, opening 19 is configured to expose a portion of insert3 to gastric fluids in the stomach such that the insert 3 erodes in adistal-to-proximal manner. As explained above, promoting the release orerosion of the insert 3 in this fashion may facilitate mechanicaldisassembly of the GRDF 10 after the predetermined time period. Again,the shape, size and location of slot 18 and opening 19 influence therelease of the API and the retention time of the GRDF 10 within thestomach.

Arms 1 and 2 may have a longest length of between 15 and 50 mm, inembodiments, between about 20 and 40 mm. Once in expanded state, thelongest length of the GRDF 10 may be more than about 15 mm, inembodiments, more than 20 mm, in other embodiments more than 25 mm, inyet other embodiments between 26 mm and 32 mm. Without compromisingother advantages of the disclosure, the longest length of arms 1 and 2may be more than 25 mm or more than 27 mm. In a collapsed state, thelongest length of the GRDF may be between 15 and 50 mm, and the diameterof the GRDF 10 (if it has a circular cross section) may be 13 mm orless. In embodiments, the diameter may be less than about 11 mm, inother embodiments less than 10 mm, in other embodiments less than 9 mmand in yet other embodiments either 9.9 mm or 8.5 mm. In the expandedconfiguration, the GRDF 10 is sized and shaped for retention within thestomach until disassembly. The geometric formation of arms 1 and 2 inthe expanded configuration of the GRDF 10 may contribute to retention ofthe GRDF 10 within the stomach. In embodiments, the GRDF 10 may betriangularly-shaped to accomplish this purpose but other geometricshapes are envisioned, e.g., any polygonal shape. In this instance,additional hinge assemblies and arms may be required to shape the GRDFonce expanded.

In embodiments, the arms 1 and 2, the hinge assembly 4 and/or thebiasing element 9 are injection molded components. In embodiments, thearms 1 and 2 and/or hinge assembly 4 may be configured to eventuallydegrade in the stomach. In other embodiments, arms 1 and 2 or hingeassembly 4 may be configured to retain their size and shape in thestomach, but, once disassembled, are easily passable through the pyloricvalve. In yet other embodiments, the arms 1 and 2 and the hinge assembly4 are made from materials that erode (or degrade) over time or uponoccurrence of a mechanical event to fully pass through the pyloric valveand the remainder of the gastrointestinal tract. Examples of suchmaterials are shown in one or more tables of the Examples disclosedherein.

In a first, collapsed and stowed configuration of the GRDF 10, the GRDF10 is of a size that is easily swallowable by a patient. As shown inFIG. 16, the GRDF 10 may be encapsulated within a dissolvable capsule20. Any biocompatible capsule known to those skilled in the art may beused to maintain the GRDF 10 in the collapsed state. The assembly of theGRDF 10 and encapsulation can be done manually or by any suitablerobotic automated machine. In FIG. 16, only one half of the dissolvablecapsule 20 is shown. The other half of capsule 20 is omitted to revealthe collapsed configuration of the GRDF 10. In this configuration, thebiasing element 9 of the GRDF 10 is collapsed between arms 1 and 2.Other retention mechanisms are contemplated to retain the GRDF 10 in acollapsed configuration for ingestion and then permit expansion of theGRDF 10 to the expanded configuration once ingested, e.g., abiodegradable band.

Once swallowed and ingested, the gastric fluids of the stomach dissolvethe capsule 20 and the biasing element 9 urges the arms 1 and 2 apart toa second, expanded configuration of the GRDF 10, e.g., as shown inFIG. 1. Once in the expanded configuration, the GRDF 10 is of a sizethat prevents the GRDF 10 from passing through the pyloric valve untildisassembly of the GRDF 10. In embodiments, the GRDF 10 is retainedwithin the stomach for a predetermined amount of time irrespective offasted or fed conditions. The predetermined amount of time may be 4hours, 6 hours, 7 hours, 8 hours, 10 hours, or 12 hours, under fastedconditions, for example. The predetermined amount of time is at least 8hours, in embodiments, 10 hours, under fed conditions, for example. Inembodiments, the predetermined amount of time the GRDF 10 is retainedwithin the stomach is at least 4 hours under fasted or fed conditions.In embodiments, the predetermined amount of time the GRDF 10 is retainedwithin the stomach is less than 18 hours under fasted or fed conditions.In embodiments, the predetermined amount of time (e.g., end point ofgastric retention) is dependent on the extent of API release or erosiontime of the insert.

As noted above, the GRDF 10 remains in the second, expandedconfiguration within the stomach until the insert or inserts 3 erode.More particularly, in an assembled form of the GRDF 10, arms 12 and 13of the hinge assembly 4 are engaged (frictionally or otherwise) betweenone of the inserts 3 and an interior wall 27 and 26 of cavities 24 and25 of the arms 1 and 2, respectively. The friction provided between thesandwiched parts maintains the GRDF 10 in an assembled condition for apre-determined amount of time inside the stomach. As the insert orinserts 3 erode and release the API (or allow the diagnostic to performits testing), the mechanical integrity of the GRDF 10 (or morespecifically the mechanical engagement of the hinge assembly 4 with thearms 1 and 2) begins to weaken and eventually fail thereby disengagingthe hinge assembly 4 from the arms 1 and 2.

For example, insert 3 of arm 2 begins to erode at the distal end thereofvia gastric fluids entering opening 19 and insert 3 of the arm 1 beginsto erode at the distal end thereof via gastric fluids entering opening21 in arm 1. In this instance, dissolution and erosion of each insert 3occurs gradually from the distal end of each insert 3 to the proximalend of each insert 3 towards the mechanical connection with hingeassembly 4. As mentioned above, gastric fluids may also enter otherslots or openings, e.g., slot 18 or opening 17, defined in the arms 1and 2 at the same time or sequentially. Once the inserts 3 havesufficiently eroded, the friction force between the sandwichedcomponents (hinge arms 12 and 13 and respective ledges 115 andengagement portions 110 of the inserts 3) is no longer sufficient tohold the individual components of the GRDF 10 together whereupon theindividual components of the GRDF 10 (hinge assembly 4, arms 1 and 2)detach from each other, thereby forming a third, disassembledconfiguration of the GRDF 10.

The individual components of GRDF 10 are sized to pass through thepyloric valve and subsequent gastrointestinal tract as two or moreseparate components (e.g., arms 1 and 2, and hinge assembly 4 or arm 1and hinge assembly 4 still joined to arm 2). As described herein, hingeassembly 4 may also include multiple components. In one embodiment, thehinge assembly 4 may be formed from and/or coated with a pH sensitiveerodible material, e.g., a material sensitive to the pH of a certainportion of the gastrointestinal tract, such that the hinge assembly 4reduces in size during transit through that portion of thegastrointestinal tract. For example, the hinge assembly 4 may include amaterial that reduces in size at a location of the gastroinstestinaltract beyond the stomach, e.g., small and/or large intestines, at a pHof about 5 to about 7.5. As can be appreciated, in the rare instancewhen the GRDF 10 is ingested and passes through the pyloric valve priorto expansion (e.g., prior to the retention mechanism (capsule 20)dissolving), constructing the hinge assembly 4 from a pH sensitiveerodible material facilitates rapid erosion of the hinge assembly 4 inthe gastrointestinal environment and initiates disassembly of the GRDFfor safe passage through the gastrointestinal tract and eventualevacuation.

In embodiments, the pH-sensitive materials may include materials whichdissolve, erode, and/or degrade at a pH higher than 5, and moreparticularly from a pH which ranges from about 5 to 7.5. Somenon-limiting examples of suitable pH-sensitive materials includepolyacrylamides, phthalate derivatives (i.e., compounds with covalentlyattached phthalate moieties) such as acid phthalates of carbohydrates,amylose acetate phthalate, cellulose acetate phthalate, other celluloseester phthalates, cellulose ether phthalates, hydroxypropyl cellulosephthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, methyl cellulose phthalate, polyvinyl acetatephthalate, polyvinyl acetate hydrogen phthalate, sodium celluloseacetate phthalate, starch acid phthalate, styrene-maleic acid dibutylphthalate copolymer, styrene-maleic acid polyvinyl acetate phthalatecopolymer, styrene and maleic acid copolymers, formalized gelatin,gluten, shellac, salol, keratin, keratin sandarac-tofu, ammoniatedshellac, benzophenyl salicylate, cellulose acetate trimellitate,cellulose acetate blended with shellac, hydroxypropylmethyl celluloseacetate succinate, oxidized cellulose, polyacrylic acid derivatives suchas acrylic acid and acrylic ester copolymers, methacrylic acid andesters thereof, vinyl acetate and crotonic acid copolymers.

The pH sensitive material may represent less than 50% of the totalweight of the body of the GRDF, in embodiments, the pH sensitivematerial may represent less than 40% of the total weight of the body ofthe GRDF, in embodiments, the pH sensitive material may represent lessthan 30% of the total weight of the body of the GRDF, in embodiments,the pH sensitive material may represent less than 20% of the totalweight of the body of the GRDF, in embodiments, the pH sensitivematerial may represent less than 10% of the total weight of the body ofthe GRDF, in embodiments, the pH sensitive material may represent lessthan 5% of the total weight of the body of the GRDF.

According to one example, once at least 70% of one or both of inserts 3have disintegrated or eroded, the individual components of the GRDF 10detach from each other. In embodiments, the individual components of theGRDF 10 disassemble once 75% of one or both inserts 3 have eroded. Inembodiments, the individual components of the GRDF 10 disassemble once80% of one or both inserts 3 have eroded. Once the inserts 3 havesufficiently disintegrated or eroded, GRDF 10 converts from an expandedconfiguration, which has a shortest length of greater than 24 mm (forexample), to a disassembled configuration including multiple detachedcomponents each having a longest length of no more than 12 mm (forexample). Each of the detached components of the GRDF is sized toquickly pass through most pyloric valves.

According to one example, during disassembly, the hinge assembly maydisengage from at least one arm once a majority of the API issubstantially released, i.e., greater than 50% of the API issubstantially released. In embodiments, the API may be substantiallyreleased from the GRDF after more than 55% of the API is released. Inembodiments, the API may be substantially released from the GRDF aftermore than 60% of the API is released. In embodiments, the API may besubstantially released from the GRDF after more than 65% of the API isreleased. In embodiments, the API may be substantially released from theGRDF after more than 70% of the API is released. In embodiments, the APImay be substantially released from the GRDF after more than 75% of theAPI is released. In embodiments, the API may be substantially releasedfrom the GRDF after more than 80% of the API is released. Inembodiments, the API may be substantially released from the GRDF aftermore than 85% of the API is released. In embodiments, the API may besubstantially released from the GRDF after more than 90% of the API isreleased. In embodiments, the API may be substantially released from theGRDF after more than 95% of the API is released.

As mentioned above, the disassembly time of the GRDF 10 can be varied bytailoring the number, size, shape and location of the openings and slotsin arms 1 and 2, respectively. For example, positioning opening 19 atthe distal end of arm 2 (and omitting slot 18) delays the erosion timeof the insert 3 which, in turn, increases the retention time of the GRDF10 in the stomach since nearly the entire length of the insert 3 musterode before the proximal end of insert 3 (engagement portion 110),which is sandwiched between arm 2 and hinge assembly 4, erodes to apoint where the GRDF 10 can no longer remain assembled, i.e., the GRDFloses mechanical integrity. Additional openings and slots in the arm 2may be added to increase the rate of erosion of the insert 3 if sodesired (see FIGS. 33 through 35). It is envisioned that any combinationof openings and slots or any combination of differently-sized openingsand slots may be utilized to expose more or less surface area of theinsert 3. As can be appreciated, the exposed surface area of the insert3 may affect the overall release rate of the API either as a directlyproportional ratio or any envisioned ratio.

It is also envisioned that one opening or slot in arms 1 and 2 may bedisposed in registration with the surface area of one API while anotheropening or slot in arms 1 and 2 may be disposed in registration with asecond or different API at a second portion of the insert 3. As can beappreciated, the opening and slots may have different dimensions tocontrol the release rate of the API as the insert erodes. The releaserate of the API may be directly proportional to the exposed surfaceareas of the insert 3, however, the release rate of one API from insert3 with the same exposed surface area may be different than the releaserate of another API from insert 3 with the same exposed surface area. Ascan be appreciated the polymers, binders and/or excipients used with theAPI to form the insert 3 may contribute to the release rate. Moreover,different ratios of polymers, binders and/or excipients for the same APImay affect the erosion rate of the insert 3 in one arm 1 compared to theerosion rate of the insert 3 in the other arm 2. Alternatively,different ratios of polymers, binders and/or excipients, etc. within asingle insert 3 that is compartmentalized with multiple APIs asexplained above may be used to affect erosion of the insert 3 and,hence, release of the API(s).

The period of time which the GRDF 10 remains in the stomach after it hasexpanded is also a function of the erosion rate of the insert 3 or theengaged portion thereof. The insert 3 may be designed to achieve aspecific erosion rate using methods which are well known in the art toobtain a desired rate of erosion of insert 3. For example, the insert 3may contain disintegration agents such as cross-linked sodiumcarboxymethyl cellulose or sodium starch glycolate to increase theerosion rate, while insert 3 may contain a quantity of binders such asPVP or HPC to decrease the erosion rate. Adjusting the rate of erosionof the insert 3 allows adjustment of the time until release of the GRDF10 from the stomach, e.g., by modulating the insert release rate,gastric retention may be controlled. Those skilled in the art willrecognize how to choose particular excipients to accomplish thispurpose.

In embodiments, the size of the GRDF 10 does not deteriorate over time,but rather is dependent on the erosion of insert 3 to initiatedisassembly, with the arms 1 and 2 and hinge assembly 4 maintainingtheir original dimensions.

In addition, the API release time of the GRDF 10 may be relatively slowand constant at least, in part, because inserts 3 are only partiallyexposed to the gastric environment. More particularly, as shown in FIGS.1-3, inserts 3 are contained in arms 1 and 2 such that the surface areaof each insert 3 is substantially concealed by the respective arms 1 and2, with the exception of the portion of inserts 3 that are exposedthrough openings/slot 17, 21 and 18, 19 in arms 1 and 2, respectively.The concealed portion of each insert 3 is not directly exposed to thechemical and mechanical effects in the gastric environment, whichtypically vary through time. The dissolution rate of the API in theinserts 3, which are substantially concealed by the arms 1 and 2, is notsubstantially influenced by the gastric environment, especially comparedto the release rate of an API provided in dosage form having a surfacearea that is completely exposed to the gastric environment. Thus, whenthe GRDF 10 is contained within the stomach, the API is released in thestomach at a relatively slow and constant rate. Moreover, by varying thenumber of and size of the openings/slot 17, 21, 19 and 18 in the arms 1and 2, the API may be released in a more controlled fashion for anydesired release profile.

As noted previously, once any of the inserts 3 described herein erodepast a certain point, the mechanical integrity of any one of the variouscomponents described herein (e.g., hinge assemblies, biasing elements,hinge arms, etc.) may be configured to fail resulting in the disassemblyof the GRDF 10.

In some embodiments, the controlled-release component of the insert 3includes a retarding polymer film. In further embodiments, thecontrolled-release component of the insert 3 includes a retardingpolymer film and an additional excipient. In still further embodiments,the additional excipient is a parting agent. In other embodiments, theadditional excipient is a pigment. In some embodiments, the retardingpolymer film includes at least one polymer or copolymer, such as, butnot limited to acrylic acid, acrylic acid derivatives, methacrylic acid,methacrylic acid derivatives, and combinations thereof. In someembodiments, the polymer film includes, but is not limited to:methacrylic acid and methacrylic acid esters, such as, but not limitedto, EUDRAGIT® L and EUDRAGIT® S; a copolymer of acrylic and methacrylicacid esters with a small amount of trimethyl ammonium methacrylate suchas EUDRAGIT® RL or EUDRAGIT® RS; a copolymer of acrylic acid andmethacrylic acid, as well as their esters (ratio of free carboxylicgroups to ester groups, e.g., 1:1), such as EUDRAGIT® L30D; or acopolymer made from acrylic acid ethyl and methacrylic acid methyl estersuch as EUDRAGIT® NE30D; or combinations thereof. By using thesepolymers as controlled-release components, a homogenous and safe releaserate is achieved.

FIGS. 8-10 depict another exemplary embodiment of a GRDF, which isdenoted by reference numeral 30. GRDF 30 is substantially similar to theGRDF 10 and only the differences between those embodiments will bedescribed. GRDF 30 generally includes a body 35 having two arms 32 and34, each of which receives an insert 36 comprising an API or adiagnostic. For the purposes herein, GRDF 30 will only be described interms of its use with an API, however, the advantages noted above withrespect to the diagnostic implementations of GRDF 10 equally apply toGRDF 30 as well. Arms 32 and 34, which are also depicted in FIG. 12, maybe structurally equivalent and are releasably coupled together by ahinge assembly 38. FIG. 11 depicts a perspective view of the hingeassembly 38. Unlike GRDF 10, GRDF 30 includes a biasing element 41 onthe hinge assembly 38, as opposed to on arm 32. Biasing element 41serves the same purpose as biasing element 9 of GRDF 10, e.g., toseparate arms 32 and 34 once the retaining mechanism (e.g., capsule) isremoved (e.g., dissolves) so that GRDF 30 can remain in the stomach fora predetermined period of time or until the occurrence of a mechanicalevent promoting disassembly.

FIG. 13 depicts another exemplary embodiment of a GRDF, which is denotedby reference numeral 40. GRDF 40 is substantially similar to GRDF 30 andonly the differences between those embodiments will be described. Unlikethe previous embodiments, GRDF 40 does not include injection moldedarms. In GRDF 40, the inserts 42 and 44, each which are composed of anAPI, serve as arms. The inserts 42 and 44 are releasably connectedtogether by a hinge assembly 46, which may be injection molded. Thehinge assembly 46 includes a biasing element 48 for biasing apartinserts 42 and 44. Hinge assembly 46 conceals at least a portion of thesurface area of inserts 42 and 44 so as to slow their dissolution in thestomach. The connection between hinge assembly 46 and inserts 42 and 44will be described with reference to the similar embodiment shown inFIGS. 14 and 15.

FIGS. 14 and 15 depict yet another exemplary embodiment of a GRDF, whichis denoted by reference numeral 50. GRDF 50 is substantially similar toGRDF 40 and only the differences between those embodiments will bedescribed. GRDF 50 includes two inserts 52 and 54, which are generallystructurally equivalent, and which are pivotably coupled together by ahinge assembly 56. Hinge assembly 56 includes a shape memory hinge 55disposed between two engagement portions 51 each having a cavity 59defined therein for receiving one of the inserts 52 and 54,respectively. As best shown in FIG. 15, each insert 52 and 54 includes agenerally bulbous proximal end 58 that is mounted within thecomplementary-shaped recess 59 defined within each engagement portion 51of the hinge assembly 56. Although FIG. 15 depicts the inserts includinga generally bulbous proximal end 58 and the engagement portionsincluding a complementary-shaped recess 59 on each end of hinge assembly56, any two complementary-shaped mechanical interfaces may be employedto releasably engage the inserts 52 and 54 with the hinge assembly 56.

Unlike GRDF 40, GRDF 50 does not include a biasing element, such aselement 48 of FIG. 13. The hinge assembly 56 of GRDF 50 may be composedof a shape memory material (SMM) such as polylactic acid, shape memoryalloy (SMA), or any other shaped memory or polymer that is known tothose skilled in the art. Shape memory alloys includecopper-zinc-aluminum-nickel, copper-aluminum-nickel, andnickel-titanium, commonly referred to in the art as NITINOL® alloys. TheSMM or SMA is configured for two-way shape memory effect. Thus, the SMMor SMA remembers two different shapes, a “cold” shape (e.g., an at-restposition) and a “hot” shape (e.g., an expanded position). Hinge assembly56 initially may be in an unexpanded position. This unexpanded, orat-rest, position corresponds to the SMM or SMA being in a cold state,that is, the SMM or SMA is in a martensite state. As SMM or SMA “heatsup,” it eventually reaches an austenite state and begins to transitionfrom the “cold” shape to the “hot” shape, which, in turn, causes hingeassembly 56 to expand. During the austenite phase transition, the hingeassembly 56 continues to expand until it reaches a threshold or finalaustenite stage. If the SMM or SMA is allowed to cool, the SMM or SMA,as its temperature decreases, will transition from the austenite stageback to the martensite stage such that the SMM or SMA will return to theunexpanded, or at-rest position. In this instance, once the capsule 20is ingested and erodes/dissolves, the hinge assembly 56 will return tothe expanded configuration and the GRDF 50 will expand for retentionwithin the stomach. As can be appreciated, no biasing element is neededto retain the GRDF 50 in the expanded configuration to avoid passagethrough the pyloric valve until disassembly.

FIG. 16 shows a GRDF, which could be any of the GRDFs 10, 30, 40 or 50that are described herein, that is encapsulated in the collapsedconfiguration within one half of a capsule 20. The other half of thecapsule has been omitted to reveal the collapsed GRDF 10, 30, 40 or 50.The capsule 20 is configured to maintain the GRDF 10, 30, 40 or 50 inthe collapsed and stowed configuration for swallowing. Once ingested,the capsule 20 sufficiently dissolves within the stomach and the GRDF10, 30, 40 or 50 springs to a deployed and expanded configuration, asdescribed previously. In embodiments, the capsule 20 or other retainingmechanism dissolves or otherwise disengages arms 1 and 2 to permitexpansion of the GRDF 10, 30, 40 or 50 to the expanded configurationwithin 10 minutes of exposure to gastric fluids, in embodiments, within5 minutes of exposure to gastric fluids, in yet other embodiments,within 2 minutes of exposure to gastric fluids. In embodiments, the GRDFautomatically transitions from the collapsed configuration to theexpanded configuration for gastric retention in less than 1, 2, 3, 4, 5,6, 7, 8, 9, or 10 minutes.

FIGS. 17A-17C and 18 depict a GRDF 60 shown in an expandedconfiguration, according to another exemplary embodiment of the presentdisclosure. GRDF 60 is substantially similar to GRDF 10 and only thedifferences between those embodiments will be described. For example,openings 19 and 21 may be defined within respective arms 62 and 64 ofthe GRDF 60. GRDF 60 includes a body 61 having two arms 62 and 64, eachconfigured to retain an insert 65 (for example, within a cavity definedtherein), and a hinge assembly 66 for connecting arms 62 and 64 togetherin a releasable and pivotable manner. GRDF 60 is capable of moving froma collapsed configuration (FIG. 19) to an expanded configuration (FIG.17A) by virtue of the spring force of a biasing element 71. As shown inFIG. 20, a collapsed GRDF 60 (FIG. 19) may be encapsulated and packagedin capsule 20.

FIG. 21 depicts a perspective view of biasing arm 62 of the GRDF 60 ofFIG. 17A. Biasing arm 62, which includes biasing element 71, issubstantially similar to arm 1 of FIG. 2 with the exception that arm 62includes two openings 68 on either side of a rectilinear slot 69 definedwithin arm 62. Openings 68 are configured to engage corresponding prongs70 (see FIG. 23A) of hinge assembly 66. Openings 68 are positionedproximal to hinge assembly 66 and on opposing sides of rectilinear slot69 on a top-facing or inner-facing surface of arm 62 from which biasingelement 71 extends. Unlike GRDF 10 of FIG. 1 which relies on friction toreleasably connect arm 1 to hinge assembly 4 (e.g., insert 3 of FIG. 1is sandwiched between hinge arm 12 and inner periphery or wall 27 ofcavity 24), arm 62 is connected to hinge assembly 66 by an interferencefit created by the engagement between openings 68 and prongs 70.

FIGS. 22A and 22B depict perspective views of arm 64 of GRDF 60. Arm 64is substantially similar to arm 2 of FIG. 2 with the exception that arm64 includes a narrow transverse slot 72 in lieu of the T-shaped slot 18disposed along arm 2 of FIG. 7. Unlike T-shaped slot 18, which directlyexposes the insert 3 contained within arm 2 to the gastric environment,slot 72 is not configured to expose insert 65 to the gastricenvironment. Rather, slot 72 releasably engages a prong 74 of hingeassembly 66 (see FIG. 23A). Also, unlike GRDF 10 of FIG. 1 which relieson friction to releasably connect arm 2 to hinge assembly 4 (e.g.,insert 3 of FIG. 1 is sandwiched between hinge arm 13 and innerperiphery or wall 26 of cavity 25), arm 64 is connected to hingeassembly 66 by an interference fit created by the engagement betweenslot 72 and prong 74. Slot 72, which may be rectilinear in shape, ispositioned proximate to hinge assembly 66.

As best shown in FIG. 22B, a recess 76 is defined on the outer surfaceof arm 64 and surrounds slot 72. Recess 76 does not pass through theentire thickness of the top facing or inner facing surface of arm 64. Asshown in FIG. 18, in an expanded configuration of the GRDF 60, a distalend 78 of the biasing element 71 engages recess 76 to prevent furthermovement of the biasing element 71 distally along arm 64. It isenvisioned that other known mechanical elements may be employed for thispurpose.

FIGS. 23A through 23D depict perspective views of hinge assembly 66 ofGRDF 60. Hinge assembly 66 includes a body 75 having two interconnectedcomponents, a first or clip portion 80 that pivotably connects to asecond or post portion 82, Hinge assembly 66 is shown in a rotatedposition in FIGS. 23A through 23D, which corresponds to the expandedconfiguration of the GRDF 60. FIGS. 24A and 24B depict perspective viewsof the clip portion 80, and FIGS. 25A and 25B depict perspective viewsof the post portion 82. As explained in further detail below, clipportion 80 and post portion 82 of hinge assembly 66 are mechanicallyengaged to one another in a clip-like fashion such that clip portion 80and post portion 82 are capable of pivoting with respect to one anotheralong a limited range of rotation (e.g., 90 degrees or less). Oncedisposed in the expanded configuration, one or both of clip portion 80and post portion 82 may include one or more mechanical features (notshown) that prevent clip portion 80 and post portion 82 from returningthe hinge assembly 66 and the GRDF 60 to the collapsed configuration.

Referring to FIGS. 24A and 24B, clip portion 80 includes a substantiallyrectangular body 81 including a C-shaped clip 86 extendingperpendicularly from a proximal end thereof and a support rib 99 thatextends perpendicularly from the proximal end thereof opposite the dipportion 86. A prong 74 is defined at a distal end of the dip portion 80and is configured for mechanical engagement with slot 72 of arm 64.Prong 74 is generally configured in the form of a triangular ramp-likesurface but any two mechanically interfacing elements are envisionedwhich will accomplish the same purpose, i.e., engage clip portion 80 toarm 64. For example, prong 74 may be provided on arm 64 and mating slot72 may be provided on clip portion 80 without departing from the scopeof the disclosure, Those skilled in the art will recognize that variousmechanisms exist for connecting arm 64 with clip portion 80, such asdamps, clips, barbs, detents, snaps, threads, fasteners and matingsurfaces.

The inner peripheral surface of C-shaped dip 86 is sized and configuredto mate with a corresponding cylindrical post 90 of post portion 82 (seeFIG. 25B). Upon assembly of the two-part hinge assembly 66, C-shaped dip86 is designed to mechanically engage post 90 in a rotatably lockingmanner, e.g., C-shaped clip 86 snaps over post 90. The interference fitbetween C-shaped clip 86 and post 90 retains the two parts of hingeassembly 66 together such that those parts are not readily capable ofdisconnection.

As shown in FIGS. 23A and 24A, support rib 99 includes asemi-cylindrical bearing surface 92 at a distal facing portion thereof(perpendicular to body 81) near the proximal end of clip portion 80.Bearing surface 92 and prong 74 are positioned on opposite sides of body81. In an assembled form of the GRDF 60, the bearing surface 92 ispositioned to abuttingly engage a proximal end 94 of insert 65 (see FIG.26), and an inner facing surface 81′ of body 81 of dip portion 80 (e.g.,FIG. 28) is positioned against a planar surface 95 of insert 65.

As best shown in FIGS. 24A and 24B, rotation limiting surfaces 96 arepositioned at the proximal end of clip portion 80 and correspondingrotation limiting surfaces 97 are positioned on a proximal end of postportion 82, In an expanded configuration of the GRDF 60, rotationlimiting surfaces 96 bear on and abuttingly engage rotation limitingsurfaces 97 to prevent over-rotation of clip portion 80 with respect topost portion 82, or vice versa (for example as shown previously in FIG.17B along the direction of the arrows). Support rib 99 extends betweenthe rotation limiting surfaces 92 and 97 to enhance the structuralintegrity of clip portion 80.

Referring now to FIGS. 23A through 23D, 25A and 25B, post portion 82also includes a substantially rectangular body 83. As mentioned above,cylindrical post 90 is provided at the proximal end of body 83 and isconfigured to engage C-shaped clip 86 of dip portion 80. Post 90 ispositioned between a pair of arms 102 that extend perpendicularly from aproximal end of body 83 of post portion 82. Each arm 102 includes theabove-described rotation limiting surfaces 97 for limiting relativerotation of the post portion 82 with respect to clip portion 80 along adefined rotational range (e.g., less than 90 degrees).

As best shown in FIGS. 18 and 23A, a semi-cylindrical bearing surface104 is defined near the proximal end of post portion 82 and isconfigured to extend perpendicularly therefrom. In an assembled form ofthe GRDF 60, bearing surface 104 is positioned against the proximal end94 of insert 65 and body 83 is positioned against a planar surface 95 ofinsert 65 (see FIGS. 26 and 31). A tab 106 at the distal end of body 83extends over insert 65, as best shown in FIGS. 18 and 31.

As best shown in FIG. 32, prongs 70 (which as mentioned above may beprovided in the form of triangular ramp surfaces) are disposed onopposing sides at the center of body 83 for engaging openings 68 of arm62. Alternatively, prongs 70 may be provided on arm 62 and the openings68 may be provided on post portion 82 without departing from the scopeof the disclosure. Those skilled in the art will recognize that variousmechanical interfaces exist for connecting arm 62 with post portion 82,such as clamps, clips, threads, fasteners and mating surfaces.

Bearing surface 104 and prongs 70 are positioned on opposite sides ofbody 83, A structural support rib 110 (see FIG. 25A) extends between thebearing surface 104 and rotational limiting surfaces 97 to enhance thestructural integrity of post portion 82.

FIGS. 27 through 29 depict an arm sub-assembly 120 of the GRDF 60including arm 64, clip portion 80 and an insert 65 in an assembledconfiguration. The arm sub-assembly 120 is configured to mechanicallyengage a corresponding arm sub-assembly 130 including arm 62, postportion 82 and a second insert 65 (see FIGS. 30-32).

As best shown in FIG. 29, clip portion 80 is sandwiched between an innerperipheral surface of arm 64 and insert 65 of arm sub-assembly 120. Aplanar surface 122 of prong 74 is positioned against a side surface ofslot 72 such that prong 74 cannot translate in the proximal direction(see arrow in FIG. 29) out of slot 72 unless and until insert 65 issufficiently eroded. More particularly, once insert 65 has sufficientlyeroded, the friction between arm 64, clip portion 80 and insert 65 isalleviated, such that those parts can detach from each other. In thismanner, the insert 65 maintains the mechanical integrity of theengagement between the clip portion 80 and the arm 64 such that, onceeroded, this mechanical integrity fails and the clip portion 80 and arm64 automatically disengage from one another.

As best shown in FIG. 28, to assemble arm sub-assembly 120, insert 65 isfirst positioned through the opening at the proximal end of arm 64 untilthe distal end of insert 65 bears on the semi-spherical surface at theend of the opening of arm 64. As mentioned above, the insert 65 and theinner peripheral surface of the arm 64 include complementary geometries(e.g., semi-cylindrical surfaces) to facilitate assembly althoughnon-complementary geometries are also envisioned depending upon aparticular purpose. The distal end of clip portion 80 is then insertedinto the narrow space defined between insert 65 and the inner peripheryor inner wall of arm 64. The inner periphery of arm 64 (which includesslot 72 defined therein) flexes to a small degree as the prong 74 ofclip portion 80 slides distally along the inner periphery of arm 64until prong 74 engages (seats within) slot 72, as shown. Once properlyengaged, prong 74 prevents clip portion 80 from moving in a proximaldirection as mentioned above (see arrow in FIG. 29).

FIGS. 30 through 32 depict arm sub-assembly 130 including arm 62, postportion 82 and a second insert 65. Post portion 82 is sandwiched betweenan inner periphery of arm 62 and second insert 65. A planar surface 124of each prong 70 is positioned against a side surface of opening 68 suchthat prongs 70 cannot translate in the proximal direction (see arrow inFIG. 31) out of openings 68 unless and until second insert 65 issufficiently eroded. More particularly, upon erosion of second insert65, the friction between arm 62, post portion 82 and second insert 65 isalleviated, such that those parts can detach from each other in thestomach. Similar to arm sub-assembly 120 described above, the secondinsert 65 maintains the mechanical integrity of the engagement betweenthe post portion 82 and the arm 62 such that, once eroded, thismechanical integrity fails and the post portion 82 and arm 62automatically disengage from one another.

As best shown in FIGS. 31 and 32, to assemble arm sub-assembly 130,second insert 65 is first positioned through an opening at the proximalend of arm 62 until the distal end of second insert 65 bears on theinterior semi-spherical surface at the end of the opening of arm 62. Asmentioned above, the second insert 65 and the inner peripheral surfaceof the arm 62 include complementary geometries (e.g., semi-cylindricalsurfaces) to facilitate assembly although non-complementary geometriesare also envisioned depending upon a particular purpose. The distal endof post portion 82 is then inserted into the narrow space definedbetween second insert 65 and the inner periphery or inner wall of arm62. The inner periphery of arm 62 (which includes openings 68 definedtherein) flexes to a small degree as the prongs 70 slide distally alongthe inner periphery of arm 62 to eventually engage (seat within)respective openings 68, as shown. Once properly engaged, prongs 70prevent post portion 82 from moving in a proximal direction (see arrowin FIG. 31) with respect to arm 62.

Once arm sub-assemblies 120 and 130 are assembled they are connectedtogether by engaging (e.g., snap-fitting) C-shaped clip 86 onto post 90.The GRDF 60 is then moved to a collapsed configuration and covered withcapsule 20 or otherwise releasably contained in a collapsed condition asdescribed above. The GRDF 60 is then ready to be swallowed by a user.

FIGS. 33 through 36B depict a GRDF 60′ according to another exemplaryembodiment of the present disclosure. GRDF 60′ is substantially similarto GRDF 60 and only the differences between those embodiments will bedescribed. Similar to GRDF 60, GRDF 60′ includes opposing arms 62′ and64′ that are configured to pivot about hinge assembly 66′ from a firstcollapsed configuration (FIG. 33) to a second expanded configuration(FIGS. 34a and 34B). Opposing arms 62′ and 64′ include a plurality ofopenings 73′ and 63′, respectively, defined therethrough configured toexpose insert 65. As mentioned above, any combination of openings may beutilized to control the erosion rate of the insert(s) 65. Arm 62′ mayinclude one or more openings e.g., openings 73′ and opening 21 at adistal end thereof, defined therethrough and positioned therealong andarm 64′ may include one or more openings e.g., openings 63′ and opening19 at a distal end thereof, defined therethrough and positionedtherealong. As can be appreciated, the number of openings and theposition of the openings along the arms 62′ and 64′ may vary.

As best shown in FIGS. 34A and 34B, a biasing element 71′ is includedthat is configured to release the GRDF 60′ to the expanded configuration(e.g., once the retention element is eroded (capsule 20 is dissolved)).Similar to the embodiments described above with respect to FIGS. 1-16,biasing element 71′ may act to lock the GRDF 60′ in the expandedconfiguration until disassembly (or, alternatively, be configured toprevent the GRDF 60′ from returning to the collapsed configuration). Assuch, once expanded, the distal end of biasing element 71′ may beconfigured to engage one of a series of recesses or slots 72′ definedwithin arm 64′. Once engaged, arm 64′ is prevented from pivoting towardsarm 62′ until disassembly.

As best shown in FIG. 35, recesses or slots 72′ are also configured toreceive prong 74′ of clip portion 80′ to releasably engage the clipportion 80′ to the arm 64′ as described in detail above with respect toFIGS. 1-33. It is envisioned that providing a plurality of recesses orslots 72′ along the proximal end of the arm 64′ may allow the clipportion 80′ to engage the arm 64′ at varying positions which, in turn,allows varyingly-sized inserts 65 to be utilized within cavity 67′.Varying the size the inserts 65 utilized within one or both arms 62′ and64′ gives the manufacturer additional flexibility as far as dosage formsand API delivery while utilizing the same arms 62′ and 64′ and hingeassembly 66′.

FIGS. 36A and 36B show varying views of the hinge assembly 66′ includingC-shaped clip portion 80′ and post portion 82′. Hinge assembly 66′ isconfigured to operate in a similar manner as described above withrespect to FIGS. 17-33 and includes similar features.

Referring generally to the figures, it should be understood that anymethod or mechanism that is configured to maintain the collapsedconfiguration of the GRDF prior to swallowing is envisioned. Severaldifferent embodiments have been described above and include a capsule 20that erodes or dissolves upon contact with gastric fluid. In anotherenvisioned embodiment, in a case where the natural state of the GRDF isopen (natural or biased configuration of one of the hinge assembliesdescribed herein is open to expand the GRDF), there may be a materialholding the GRDF closed which dissolves or erodes in the presence ofgastric fluid thereby releasing the GRDF to an expanded configuration.In another embodiment, the material may be in the shape of an erodibleband which encompasses the arms to maintain the GRDF in a collapsedconfiguration until the band erodes allowing expansion of the GRDF.Still another envisioned embodiment includes a glue-like material thatkeeps the two arms together until the glue-like material erodes allowingexpansion of the GRDF. Another option may be the capsule itself whichmaintains the closed state. In embodiment, the capsule maintains a shelflife durability or shelf life stability for more than 2 years underaccelerated conditions.

It should be understood that any method or mechanism that is configuredto transition or open the GRDF to the expanded configuration isencompassed by the present disclosure. In one envisioned embodiment, asuperporous hydrogel system may be incorporated into the inner part ofthe arms which expands upon exposure to the gastric environment therebyforcing the two arms apart and to the expanded configuration. In anotherembodiment, a leaf spring (similar to those described above) springsoutwards and extends from the inner area of one or both of the arms oncethe expanding configuration is initiated or once the mechanicalintegrity of the collapsed condition has been compromised, e.g., capsule20 is dissolved. In other embodiments, various mechanisms may beemployed to lock the arms in an expanded configuration until the inserthas sufficiently erodes to disassemble the GRDF. For example, asdescribed above, an inner facing surface of one of the arms may includea locking mechanism to lock the leaf spring in place in the expandedconfiguration. Alternatively and in addition to the hinge assembliesdescribed above, the hinge assembly may include one or more mechanicalinterfaces or mechanisms, gear, spring, cam, etc. that are configured tomaintain or lock the GRDF in an expanded configuration untildisassembly. The leaf spring may simply be configured to bias the GRDFfrom the collapsed configuration and not necessarily lock to maintainthe GRDF in the expanded configuration but may be configured to simplyprevent the GRDF from transitioning back to the collapsed configuration.

In embodiments described herein, the leaf spring or biasing mechanism 9may be configured to lock the two arms in the expanded configurationuntil disassembly. One or more locking mechanisms may be employed forthis purpose, or, alternatively, the leaf spring may be configured toengaged one of the arms to keep the two arms apart until disassembly. Inother embodiments, the biasing mechanism, e.g., leaf spring 9, may beconfigured to engage the opposing arm 2 to keep the two arms 1 and 2separated as the insert 3 slowly erodes. As the insert 3 erodes (API isreleased), the bias of the leaf spring 9 gradually lessens or the leafspring 9 regresses into the arm 2 such that the angle β between the twoarms 1 and 2 lessens to a point when the size or formation (e.g.,triangular shape) of the GRDF 10 is small enough to pass through thepyloric valve in the stomach. As can be appreciated, in this instancethe GRDF does not necessarily need to disassembly for it to safely passthrough the pyloric valve.

As noted above, after a pre-determined period of time, the GRDFsdescribed herein will eventually lose their mechanical integrity as asingle unit, disassemble and pass from the stomach for subsequentevacuation. There are many possible mechanisms to achieve this result,all of which are encompassed by the present disclosure. Non-limitingexamples include:

-   -   Hinge assemblies or other connection mechanisms composed of one        or more base-sensitive materials which begin to disintegrate or        erode once exposed to the proximal end of the arm's internal        matrix (the API release system) which includes basic material.    -   Hinge assemblies or other connection mechanisms composed of one        or more time sensitive polymers which begin to disintegrate at a        certain point in time.    -   Hinge assemblies or other connection mechanisms connected to the        arms in a certain mechanical fashion, with a certain mechanical        shape or by one or more mechanical features such that once the        arms, insert or hinge assembly erode via the introduction of        gastric fluids, the mechanical integrity of the hinge assembly        or arms (or parts thereof) is compromised due to a change of        shape of one or more mechanical elements and, as a result, the        mechanical engagement is lost.

Optionally, in an additional embodiment, any of the GRDFs described orenvisioned herein may include an emergency release feature that allowsthe GRDF to pass through the pyloric valve for immediate removal fromthe stomach and gastrointestinal tract, if needed. An antidote or othertriggering mechanism may be employed to initiate the emergency releaseof the GRDF. In one envisioned embodiment, the GRDF includes a hingeassembly (or any other portion thereof) that is pH sensitive (forexample sensitive to a pH 5-5.5) such that under normal gastricconditions the hinge assembly (or any portion thereof) remains intactand the GRDF functions as intended. However, if needed, theenvironmental pH can be slightly increased (to within the above pHsensitive range or any other specified range) causing the mechanicalintegrity of the hinge assembly (or any portion thereof) to erodecausing the hinge assembly to disassemble from one or both arms and passthrough the pyloric valve for subsequent evacuation. For example, theerosion may cause reduced mechanical pressure between the insert and thehinge assembly (or a portion thereof) to eventually release the hingeassembly from one or both arm(s) and pass from the stomach.

As mentioned above, the GRDF may be configured for use with one or moreadditional APIs with different release profiles, e.g., an additional APIdesigned for immediate release. The additional API, (e.g., an APIdesigned for immediate release) may be located at the distal end of theinsert and used with a GRDF with an opening at a distal end of one orboth arms. In this instance, the configuration of the GRDF along withthe API being disposed at a distal end of the insert directs the initialinfusion of gastric fluids into the distal opening of the one or botharms and into immediate contact with the additional API promotingimmediate release. In another embodiment, additional API may be includedas a layer encompassing the capsule or surrounding the GRDF, or a layerencompassing one or both arms (or portions thereof). In embodiments, theamount of API in the GRDF is a therapeutically effective amount fortreating a particular disease or condition over a prescribed timeperiod, e.g., hourly (q1 h), q2 h—q8 h, b.d.s., and o.d.

Any relevant amount of API is encompassed by the present disclosure. Theamount of API depends on a variety of factors such as the need foradditional excipients and the size of tablet. In embodiments, an amountof API contained in the GRDF may be from about 0.1 mg to about 2 grams,in embodiments from about 10 mg to about 1.8 grams. In otherembodiments, the amount of API present in the insert may be an amountgreater than 400 mg, 600 mg, 800 mg, 1000 mg, or 1500 mg. Inembodiments, the API is in an amount of about 500 mg to about 1.5 grams.

The GRDFs described herein may include a body which includes a volumeranging from about 100 mm³ to about 2000 mm³. In embodiments, the volumeof the body may range from about 200 mm³ to about 1800 mm³. Inembodiments, the volume of the body may range from about 500 mm³ toabout 1500 mm³. In embodiments, the volume of the body may range fromabout 800 mm³ to about 1200 mm³. In embodiments, the volume of the bodymay be about 950 mm³.

The GRDFs described herein are designed to maximize the API to totalexcipients volume/weight ratio, in an effort to maximize the drugvolume/weight load to be processed in the stomach while minimizing thevolume of non-drug material that must pass through the gastrointestinaltract. According to one aspect of the disclosure, a ratio of a weight ofthe active pharmaceutical ingredients to a weight of total excipients isfrom about 0.8 to about 0.05, in embodiments, from about 0.7 to about0.3, and in other embodiment, from about 0.6 to about 0.4. The totalexcipients may include the arms, the hinge, the excipients in theinsert, and the capsule. In embodiments, the load of the excipients maybe from about 500 mg to about 2000 mg, and the drug volume may be fromabout 900 mg to about 1000 mg.

The GRDFs described herein are designed to maximize the API to totalexcipients ratio, in an effort to maximize the drug API load (mg) whileminimizing the load of non-drug material (mg) that must pass through thegastrointestinal tract. According to one aspect of the disclosure, theratio of a load (mg) of the active pharmaceutical ingredients to a loadof total load of the insert tablet (excipients+API) in the insert isfrom about 0.1 to about 0.99, in embodiments, from about 0.5 to about0.95, and in other embodiments from about 0.7 to about 0.9.

One or more APIs or diagnostics for controlled release may be associatedwith the GRDF in a variety of ways, depending on the physical andchemical properties of the API or diagnostic and the desired releaseprofile. In one example, the API or diagnostic may be at least partiallyenclosed within an external polymeric layer which forms the perimeter ofthe arm(s) and which at least partially defines an interior cavityconfigured to hold a API/diagnostic and excipients. The API/diagnosticand excipients may be contained within the polymeric layer forming thecavity. The excipients may be any pharmaceutically excipients including,but not limited to, an erodible polymer matrix or may make up aconstant-flow pump, which is for example mechanically or osmoticallydriven. As described above, the cavity may also have openings whichcontribute to a controlled release effect. In another example, thecontrolled release effect may be achieved by another method known in theart other than a polymeric layer forming a shell. As mentioned above,the arms may also be rigid and contain API (or API and excipients). Inembodiments, the API may not be contained within an insert but may, forexample, the API may be formulated to simply form part of the armitself. Similar to the various embodiments described herein, the insertcan be disengaged from the arms in any a number of different ways, e.g.,an erodible polymer linking the arms to the hinge that disengages thearms in a time dependent manner.

Each of the GRDFs described above provides mechanical strength and iscapable of resisting forces applied by the stomach under both fed andfasted condition. The mechanical strength is sufficient to enable, uponexpansion of the GRDF, the preservation of the expanded configuration toprovide gastric retention. More specifically, there is provided a GRDFwith collapsed and expanded configurations which resists mechanicalgastric forces.

The choice of materials for GRDFs includes all materials that willmaintain stability in the gastric environment and provide enoughrigidity to prevent disassembly or disintegration prior to the desiredtime (preferably through fasted and fed states). Any acceptablepharmaceutically approved polymeric materials such as cellulose acetate,ethocel, eudragit, or hydroxypropyl cellulose acetate succinate, with orwithout addition of a plactisizer, can be used for preparation of theGRDF. If the desire is a non-biodegradable formulation, one may provide,for example, a cellulose ester with plasticizer. Suitable celluloseesters include for example: cellulose acetate, cellulose acetatebutyrate and cellulose acetate propionate. Non-limiting examples ofsuitable plasticizers include, for example, dibutyl sebacate, triacetin,triethyl-citrate, acetyl tributyl citrate, acetyl triethyl citratepolyethylene glycol, polyethylene glycol monomethyl ether, glycerin,sorbitol sorbitan solutions, castor oil, diacetylated monoglycerides,triethyl citrate, tributyl citrate or others.

The materials are selected and processed in a way that will enable eachof the components of the GRDF to operate according to its definedfunctionality (e.g., rigidity for the arms and hinge, elasticity ofspring, and stability in dissolution, as defined above). Differentmaterials may be used in order to better balance between durability andsafety or eventual disintegration; pH independence and dependence, etc.For example, the ratio of cellulose acetate (CA) to triacetin maycontribute to the durability, elasticity, reduced brittleness,independence from pH changes and decreased erodability. In embodiments,the cellulose acetate (CA) to triacetin ratio is 3:1 to 10:1, or inother embodiments 4:1 to 8:1.

In embodiments, the pharmaceutically acceptable material may include acomposition which includes a cellulose ester and a plasticizer in aratio ranging from about 3:1 to about 8:1, in embodiments, from about4:1 to about 6:1, and in particular embodiments 4:1.

In embodiments, the hinge assembly and or arms may be comprised of:plasticizer and any one or more of the following: cellulose ester, HPMCacetate succinate, ethocel or eudragit. The plasticizer may be any oneor more of the following: trethyl citrate, PEG 3350, triacetin andtriethyl citrate. More specifically, the cellulose ester may becellulose acetate (CA). The polymer to cellulose acetate (CA) ratio maybe from about 3:1 to about 10:1, or in other embodiments from about 4:1to about 8:1. Dibutyl Sebacate, Triacetin, Triethyl-citrate, AcetylTributyl Citrate, Acetyl Triethyl Citrate Polyethylene glycol,Polyethylene Glycol Monomethyl Ether, Glycerin, Sorbitol SorbitanSolutions, Castor Oil, Diacetylated Monoglycerides, Triethyl Citrate,Tributyl Citrate.

In embodiments, the GRDF including any of the components of the GRDF,i.e., the body, arms, hinge assembly, etc., may include more than about200 mg, 400 mg, 600 mg, 700 mg, or 750 mg of the cellulose ester perunit dosage form. In other embodiments, the GRDF including any of thecomponents of the GRDF, i.e., the body, arms, hinge assembly, etc., mayinclude from about 100 mg to about 800 mg of the cellulose ester perunit dosage form.

In embodiments, the GRDF including any of the components of the GRDF,i.e., the body, arms, hinge assembly, etc., may include more than 50 mg,100 mg, 150 mg, 180 mg, 190 mg of the plasticizer per unit dosage form.In other embodiments, the GRDF including any of the components of theGRDF, i.e., the body, arms, hinge assembly, etc., may include from about25 mg to about 250 mg of the plasticizer per unit dosage form.

The gastric retention may be attained due to the arms and hingeassembly, while the structure of the arms (with slight modifications offormulation of the insert depending on length of time needed) providefor the controlled release of the API or diagnostic.

The GRDFs may be manufactured by a number of processes includinginjection molding 3D printing and the like, as will be clear to oneskilled in the art, such as the manufacturing techniques described in WO2003057197 or in Zema et. al., Journal of Controlled Release, Volume 159(2012) 324-331. For example, a mold can be constructed in the desiredshape of the GRDF and filled with appropriate material(s) in liquidstate and then allowed to cure by chemical processes or cooled ifthermosetting material(s) are used. The GRDFs described herein or anyparts thereof, e.g., arms, hinge assembly, springs, etc. may be madefrom pharmaceutically acceptable materials or ingredients, e.g., one ormore ingredients listed in the IIG guidelines. In embodiments, the GRDFmay include a body which is made from at least one pharmaceuticallyacceptable material wherein the size, shape, and durability of the bodyare maintained while in the stomach for a predetermined time period ofgastric retention. The use of injection molding applied to the specifiedingredients in the specified molds resulted in less than 10% variation,in embodiments, less than 5% variation, in detail as small as 500 μm.

In embodiments, the GRDF, including any of the components of the GRDF,i.e., the body, arms, hinge assembly, etc., may include a mechanicaldurability to remain intact, i.e., assembled, over a period of time ofat least 1 hour and under the application of a repetitive force of atleast 400 grF. In embodiments, the GDRF may include a mechanicaldurability to remain intact over a period of time of at least 2, 3, 6,9, 12 and 24 hours and under the application of a repetitive forceranging from about 400 grF to about 3000 grF, in embodiments from about400 grF to about 1250 grF.

In yet another embodiment there is provided a method for treating apatient in need of extended retention of an API or diagnostic in thestomach by administering an oral pharmaceutical dosage form to thepatient including an API or diagnostic for extended retention in astomach for a pre-determined number of hours under fasted or fedconditions. The oral pharmaceutical dosage form may be any of the GRDFsthat are described herein.

From the foregoing and with reference to the various figure drawings,those skilled in the art will appreciate that certain modifications canalso be made to the present disclosure without departing from the scopeof the same.

For example, the present disclosure also relates to an oralpharmaceutical that includes an API or diagnostic configured forextended retention in a stomach for at least 4 hours under fastedconditions. In embodiments, the API is configured for retention in thestomach for at least 6 hours under fasted conditions. Still, in otherembodiments, the API is configured for retention in the stomach for atleast 8 hours under fasted conditions, in embodiments, at least 10 hoursunder fasted conditions, and in yet other embodiments, at least 12 hoursunder fasted conditions.

The present disclosure also relates to an oral pharmaceutical thatincludes an API or diagnostic configured for extended retention in astomach for at least 8 hours under fed conditions, in embodiments, atleast 10 hours under fed conditions.

In embodiments, the retention in the stomach has an end point in timethat is dependent on the extent of drug release. The API may be in anamount within the range of about 0.1 milligrams to about 2.0 grams, inembodiments, about 0.1 milligrams to about 2.0 grams, in embodiments,about 0.2 milligrams to about 1.9 grams, in embodiments, about 0.3milligrams to about 1.8 grams, in embodiments, about 0.4 milligrams toabout 1.7 grams, in embodiments, about 0.5 milligrams to about 1.6grams, in embodiments, about 0.6 milligrams to about 1.5 grams, inembodiments, about 0.7 milligrams to about 1.4 grams, in embodiments,about 0.8 milligrams to about 1.3 grams, in embodiments, about 0.9milligrams to about 1.2 grams, in embodiments, about 1 milligrams toabout 1.1 grams, in embodiments, about 2 milligrams to about 1 gram, inembodiments, about 5 milligrams to about 900 milligrams, in embodiments,about 10 milligrams to about 800 milligrams, in embodiments, about 20milligrams to about 700 milligrams, in embodiments, about 50 milligramsto about 600 milligrams, in embodiments, about 100 milligrams to about500 milligrams, in embodiments, about 200 milligrams to about 400milligrams, in embodiments, about 250 milligrams to about 400milligrams, in embodiments, about 300 milligrams to about 400milligrams. One or more controlled release excipients may be providedthat control the release of the API.

The present disclosure also relates to one or more methods for treatinga patient in need of extended retention of an active pharmaceuticalingredient (API) or diagnostic in the stomach and at least includesadministering an oral pharmaceutical including an API or diagnostic forextended retention in a stomach for at least four hours under fasted andfed conditions.

The present disclosure also relates to a GRDF including a body havingtwo or more arms and configured to transform between a collapsedconfiguration for ingestion and an expanded configuration for retentionwithin the stomach for a predetermined time period. The arms arepivotable from the collapsed configuration to the expanded configurationwithin 5 minutes of ingestion to a size sufficient for gastricretention.

The present disclosure also relates to a GRDF including a hinged bodyconfigured to transform between a collapsed configuration for ingestionand an expanded configuration for retention within the stomach for apredetermined time period. The hinged body is transformable from thecollapsed configuration to the expanded configuration within 5 minutesof ingestion to a size sufficient for gastric retention.

The present disclosure also relates to a GRDF including a body having atleast two arms and an active pharmaceutical ingredient (API) retainedwithin at least one of the two arms. After exposure to simulated gastricconditions for 24 hours the two arms dissemble upon a force greater 400grF.

The present disclosure also relates to a GRDF including a body having atleast one of a hinge assembly or a pair of arms and an API retainedwithin at least one of the pair of arms. The body is configured toendure up to 3000 grF without disassembly before the release of the API.The body is configured to disassemble at a force greater than 400 grFfollowing the release of at least 90% of the API, in embodiments, atleast 80% of the API, in other embodiments, at least 70% of the API.

The present disclosure also relates to a GRDF including a body made of apharmaceutically acceptable material and having an initial size and aninitial strength, wherein the initial size and initial strength of thebody is maintained after at least 24 hr under simulated gastricconditions such that the GRDF cannot pass the 18 mm pipe test (SeeExperiment 2 above) under 300 grForce.

The present disclosure also relates to a GRDF including a body made of apharmaceutically acceptable material and including an API having a sizeand a strength that is maintained after more than 85% of the API isreleased, such that the GRDF cannot pass the 18 mm pipe test under 300grForce.

The present disclosure also relates to GRDF including a body having afirst arm and a second arm configured to move between a collapsedconfiguration for ingestion to an expanded configuration for retentionin the stomach. The GRDF also includes an API retained within at leastone of the two arms, wherein the body in the expanded configurationprovides prolonged gastric retention, e.g., retention more than 24hours, more than 36 hours, more than 48 hours, 2-180 days, 3-120 days,3-90 days, etc.

The present disclosure also relates to GRDF including an immediaterelease composition comprising an API or diagnostic, the compositionpositioned in a cavity defined within a body.

The present invention also relates to a gastroretentive drug form (GRDF)for extended retention in a stomach that includes a body having firstand second arms. One or both of the arms include: a cavity definedtherein configured to receive an erodible insert; and one or moreopenings defined therein configured to expose the insert (or a portionthereof) to gastric fluids. A biasing element is included that isconfigured to move the first and second arms relative to one another. Ahinge assembly releasably engages the first and second arms and isconfigured to allow the first and second arms to pivot relative to oneanother from a first configuration in close proximity to one another toa second configuration further from one another. The hinge assembly (ora portion thereof) is releasably engaged between at least one of thearms that includes the cavity and the insert. Upon introduction of theGRDF into the stomach, the biasing element moves the first and secondarms from the first configuration and gastric fluids access the openingto erode the exposed portion of the insert over time wherein the hingeassembly (or the portion thereof that engages the insert) disengagesfrom the insert and initiates disassembly of the first and second armsfrom the hinge assembly.

In embodiments, the biasing element maintains the first and second armsin the second configuration. The second configuration of the first andsecond arms retains the GRDF within the stomach until disassembly. Thebiasing element may be operably coupled to one of the first and secondarms, form part of the hinge assembly, or be a portion of a livinghinge. The biasing element may be a spring (e.g., leaf spring) or asuperporous hydrogel.

In yet other embodiments, the GRDF may include a retention elementconfigured to maintain the first and second arms in the firstconfiguration prior to ingestion and release the first and second armsafter ingestion. The retention element may be biodegradable, e.g., (abiodegradable capsule or band) and/or may be configured to encapsulateat least a portion of the body.

In embodiments, the first and second arms include a size and a shapesuch that, when disposed in the first configuration, the size and shapeof the first and second arms are suitable for swallowing. When disposedin the second configuration, the first and second arms may include asize, a shape and a formation such that at least one of the size, shapeand formation of the first and second arms contributes to retention ofthe GRDF within the stomach.

In yet further embodiments, the hinge assembly (or a portion thereof) isreleasably engaged between at least one arm including the cavity and theinsert is disposed at the proximal end of the arm. In still otherembodiments, the hinge assembly (or a portion thereof) is frictionallyengaged between the arm including the cavity and the insert. The hingeassembly (or a portion thereof) may be mechanically engaged to the armincluding the cavity and frictionally engaged to the insert.

The one or more openings may be defined in a distal end of the arm suchthat the insert erodes in a distal-to-proximal manner. The one or moreopenings may be a slot defined within an inner-facing surface of one ofthe arms. The size, shape or position of the one or more openings may beconfigured to control a rate of erosion of the insert. The exposedsurface area and disposition of the insert at least partially controlsthe rate of erosion of each active pharmaceutical ingredient of theinsert.

In embodiments, the insert may include one or more active pharmaceuticalingredients. Two or more of the active pharmaceutical ingredients mayhave different erosion rates. In still other embodiments, one of thearms includes at least two openings defined therein which are disposedin vertical registration with at least two active pharmaceuticalingredients having the same or different erosion rates. The size, shapeand position of the at least two openings at least partially controlsthe rate of erosion of each active pharmaceutical ingredient of theinsert.

In other embodiments, the body, biasing element and/or hinge assemblyare made from pharmaceutically acceptable materials. The body, biasingelement and/or hinge assembly may be manufactured from injectionmoldable materials.

In embodiments, gastric fluids erode about 80%, or in embodiments, 70%,of the insert over a predetermined time period to initiate detachment ofthe insert from the hinge assembly (or a portion thereof) anddisassembly of the first and second arms from the hinge assembly.

In still other embodiments, at least a portion of the hinge assembly,biasing element, and/or a portion of the body (e.g., first and secondarms) is made from a pH sensitive material configured to at leastpartially erode in the gastrointestinal tract. At least a portion of thehinge assembly may be made from a material that erodes within a pHsensitive range such that the hinge assembly at least partially erodesand detaches from at least one of the first and second arms upon contactwith a pH within the pH sensitive range.

The present disclosure also relates to a gastroretentive drug form(GRDF) for extended retention in a stomach, including a body havingfirst and second arms. At least one of the arms includes: a cavitydefined therein configured to receive an erodible insert; and one ormore openings defined therein configured to expose at least a portion ofthe insert to gastric fluids. A hinge assembly is included thatreleasably engages the first and second arms and is configured to biasthe first and second arms relative to one another from a firstconfiguration in close proximity to one another to a secondconfiguration further from one another. The hinge assembly (or a portionthereof) is configured to releasably engage between the arm includingthe cavity and the insert. Upon introduction of the GRDF into thestomach, the hinge assembly moves the first and second arms from thefirst configuration and gastric fluids access the opening to erode theexposed portion of the insert over time wherein the hinge assembly (or aportion thereof) disengages from the insert and initiates disassembly ofthe first and second arms from the hinge assembly.

In embodiments, the hinge assembly maintains the first and second armsin the second configuration. When in the second configuration, the firstand second arms retain the GRDF within the stomach until disassembly.

In yet other embodiments, the GRDF may include a retention elementconfigured to maintain the first and second arms in the firstconfiguration prior to ingestion and release the first and second armsafter ingestion. The retention element may be biodegradable, e.g., abiodegradable capsule or band, and/or may be configured to encapsulateat least a portion of the body.

In embodiments, the first and second arms include a size and a shapesuch that, when disposed in the first configuration, the size and shapeof the first and second arms are suitable for swallowing. When disposedin the second configuration, the first and second arms may include asize, a shape and a formation such that at least one of the size, shapeand formation of the first and second arms contributes to retention ofthe GRDF within the stomach.

In yet further embodiments, the hinge assembly (or a portion thereof) isreleasably engaged between the arm including the cavity and the insertis disposed at the proximal end of the arm. In still other embodiments,the hinge assembly (or a portion thereof) is frictionally engagedbetween the arm including the cavity and the insert. The hinge assembly(or a portion thereof) may be mechanically engaged to the arm includingthe cavity and frictionally engaged to the insert.

The one or more openings may be defined in a distal end of the arm suchthat the insert erodes in a distal-to-proximal manner. The one or moreopenings may be a slot defined within an inner-facing surface of one ofthe arms. The size, shape or position of the one or more openings may beconfigured to control a rate of erosion of the insert. The exposedsurface area and disposition of the insert at least partially controlsthe rate of erosion of each active pharmaceutical ingredient of theinsert.

In embodiments, the insert may include one or more active pharmaceuticalingredients. Two or more of the active pharmaceutical ingredients mayhave different erosion rates. In still other embodiments, one of thearms includes at least two openings defined therein which are disposedin vertical registration with at least two active pharmaceuticalingredients having the same or different erosion rates. The size, shapeand position of the at least two openings at least partially controlsthe rate of erosion of each active pharmaceutical ingredient of theinsert.

In other embodiments, the body and/or hinge assembly are made frompharmaceutically acceptable materials. The body and/or hinge assemblymay be manufactured from injection moldable materials.

In embodiments, gastric fluids erode about 80%, or in embodiments, 70%,of the insert over a predetermined time period to initiate detachment ofthe insert from the hinge assembly (or a portion thereof) anddisassembly of the first and second arms from the hinge assembly.

In still other embodiments, at least a portion of the hinge assemblyand/or a portion of the body (e.g., first and second arms) is made froma pH sensitive material configured to at least partially erode in thegastrointestinal tract. At least a portion of the hinge assembly may bemade from a material that erodes within a pH sensitive range such thatthe hinge assembly at least partially erodes and detaches from at leastone of the first and second arms upon contact with a pH within the pHsensitive range.

The present disclosure also relates to a gastroretentive drug form(GRDF) for extended retention in a stomach that and includes a bodyhaving one or more openings defined therein configured to expose atleast a portion of an insert contained therein to gastric fluids. Ahinge assembly is configured to allow the body to move from a collapsedconfiguration to an expanded configuration and at least a portion of thehinge assembly is releasably engaged between the body and the insert.Upon introduction of the GRDF into the stomach, the body transitionsfrom the collapsed configuration and gastric fluids access the openingto erode the exposed portion of the insert over time wherein the atleast a portion the hinge assembly disengages from the insert andinitiates disassembly of the body from the hinge assembly.

In embodiments, the GRDF may include a retention element configured tomaintain the body in the first configuration prior to ingestion andtransition the body to the expanded configuration after ingestion. Theretention element may be biodegradable, e.g., a biodegradable capsule orband, and/or may be configured to encapsulate at least a portion of thebody.

In embodiments, the body includes a size and a shape such that, whendisposed in the first configuration, the size and shape of the body issuitable for swallowing. When disposed in the second configuration, thebody may include a size, a shape and a formation such that at least oneof the size, shape and formation of the body contributes to retention ofthe GRDF within the stomach.

In yet further embodiments, the hinge assembly (or a portion thereof) isreleasably engaged between the body (or a cavity defined within thebody) and the insert. In still other embodiments, the hinge assembly (ora portion thereof) is frictionally engaged between body and the insert.The hinge assembly (or a portion thereof) may be mechanically engaged tothe body and frictionally engaged to the insert.

The one or more openings may be defined in a distal end of the body suchthat the insert erodes in a distal-to-proximal manner. The one or moreopenings may be a slot defined within an inner-facing surface of thebody. The size, shape or position of the one or more openings may beconfigured to control a rate of erosion of the insert. The exposedsurface area and disposition of the insert at least partially controlsthe rate of erosion of each active pharmaceutical ingredient of theinsert.

In embodiments, the insert may include one or more active pharmaceuticalingredients. Two or more of the active pharmaceutical ingredients mayhave different erosion rates. In still other embodiments, the body mayinclude at least two openings defined therein which are disposed invertical registration with at least two active pharmaceuticalingredients having the same or different erosion rates. The size, shapeand position of the at least two openings at least partially controlsthe rate of erosion of each active pharmaceutical ingredient of theinsert.

In other embodiments, the body and/or hinge assembly are made frompharmaceutically acceptable materials. The body and/or hinge assemblymay be manufactured from injection moldable materials.

In embodiments, gastric fluids erode about 80%, or in embodiments, 70%,of the insert over a predetermined time period to initiate detachment ofthe insert from the hinge assembly (or a portion thereof) anddisassembly of the body from the hinge assembly.

In still other embodiments, at least a portion of the hinge assemblyand/or a portion of the body is made from a pH sensitive materialconfigured to at least partially erode in the gastrointestinal tract. Atleast a portion of the hinge assembly may be made from a material thaterodes within a pH sensitive range such that the hinge assembly at leastpartially erodes and detaches from the body upon contact with a pHwithin the pH sensitive range.

The present disclosure also relates to a gastroretentive drug form(GRDF) for extended retention in a stomach, including a body havingfirst and second arms and including a cavity defined therein configuredto receive an erodible insert. The body includes at least one openingdefined therein configured to expose at least a portion of the insert togastric fluids. Upon introduction of the GRDF into the stomach, the bodytransitions from a collapsed configuration to an expanded configurationand gastric fluids access the opening to erode the exposed portion ofthe insert over time and initiates disassembly of the first and secondarms from the body.

In embodiments, at least one of the shape, size and formation of thefirst and second arms in the expanded configuration retains the GRDFwithin the stomach until disassembly.

In embodiments, the GRDF may include a retention element configured tomaintain the body in the first configuration prior to ingestion andtransition the body to the expanded configuration after ingestion. Theretention element may be biodegradable, e.g., a biodegradable capsule orband, and/or may be configured to encapsulate at least a portion of thebody.

In embodiments, the body includes a size and a shape such that, whendisposed in the first configuration, the size and shape of the body issuitable for swallowing. When disposed in the second configuration, thebody may include a size, a shape and a formation such that at least oneof the size, shape and formation of the body contributes to retention ofthe GRDF within the stomach.

In yet further embodiments, the hinge assembly (or a portion thereof) isreleasably engaged between the body (or a cavity defined within thebody) and the insert. In still other embodiments, the hinge assembly (ora portion thereof) is frictionally engaged between body and the insert.The hinge assembly (or a portion thereof) may be mechanically engaged tothe body and frictionally engaged to the insert. In yet otherembodiment, the hinge assembly is a portion of a living hinge.

The one or more openings may be defined in a distal end of the body suchthat the insert erodes in a distal-to-proximal manner. The one or moreopenings may be a slot defined within an inner-facing surface of thebody. The size, shape or position of the one or more openings may beconfigured to control a rate of erosion of the insert. The exposedsurface area and disposition of the insert at least partially controlsthe rate of erosion of each active pharmaceutical ingredient of theinsert.

In embodiments, the insert may include one or more active pharmaceuticalingredients. Two or more of the active pharmaceutical ingredients mayhave different erosion rates. In still other embodiments, the body mayinclude at least two openings defined therein which are disposed invertical registration with at least two active pharmaceuticalingredients having the same or different erosion rates. The size, shapeand position of the at least two openings at least partially controlsthe rate of erosion of each active pharmaceutical ingredient of theinsert.

In other embodiments, the body and/or hinge assembly are made frompharmaceutically acceptable materials. The body and/or hinge assemblymay be manufactured from injection moldable materials.

In embodiments, gastric fluids erode about 80%, or in embodiments, 70%,of the insert over a predetermined time period to initiate detachment ofthe insert from the hinge assembly (or a portion thereof) anddisassembly of the body from the hinge assembly.

In still other embodiments, at least a portion of the hinge assemblyand/or a portion of the body is made from a pH sensitive materialconfigured to at least partially erode in the gastrointestinal tract. Atleast a portion of the hinge assembly may be made from a material thaterodes within a pH sensitive range such that the hinge assembly at leastpartially erodes and detaches from the body upon contact with a pHwithin the pH sensitive range.

The present disclosure also relates to a gastroretentive drug form(GRDF) for extended retention in a stomach that includes a bodyincluding first and second arms, at least the first arm having: a cavitydefined therein configured to receive an erodible insert; at least oneopening defined therein configured to expose at least a portion of theinsert to gastric fluids; and a hinge assembly including a first portionreleasably engaged to the first arm and a second portion releasablyengaged to the second arm. The first and second portions are operablycoupled to one another and configured to bias the first and second armsrelative to one another from a first configuration in close proximity toone another to a second configuration further from one another. Thefirst portion is releasably engaged between the first arm and theinsert. Upon introduction of the GRDF into the stomach, the hingeassembly moves the first and second arms from the first configurationand gastric fluids access the opening to erode the exposed portion ofthe insert over time wherein the first portion disengages from theinsert and initiates disassembly of the first and second arms from thehinge assembly.

In embodiments, the first portion includes a mechanical interface thatmatingly engages a corresponding mechanical interface disposed on thesecond portion to permit pivotable motion of the first portion relativeto the second portion. The first portion may be a C-shaped clip and thesecond portion may include a post configured to receive the C-shapedclip in a snap-fit manner.

In embodiments, the first portion includes a rotation limiting surfaceto prevent over-rotation of the first and second portions relative toone another. At least one of the first and second portions includes amechanical interface that is configured to releasably engage acorresponding mechanical interface disposed on at least one of the firstand second arms. The mechanical interface on at least one of the firstand second portions may include a prong and the corresponding mechanicalinterface disposed on at least one of the first and second arms mayinclude an opening defined therein that complements the prong.

In embodiments, the amount of the API is shared evenly in each of thearms. In other embodiments, the amount of the API is not shared evenlyin each of the arms.

A method of assembling a gastroretentive dosage form (GRDF) is providedin accordance with the present disclosure and includes: inserting aninsert tablet into a cavity of a body formed by injection molding; andcombining the body with a hinge assembly.

A method of delivery of an API or diagnostic is provided in accordancewith the present disclosure that includes administering to a patient aGRDF of any of the previous claims in a closed configuration.

A method of manufacturing a dosage form for gastric retention isprovided in accordance with the present disclosure that includes forminga body of the dosage form including a cellulose ester composition.

In embodiments, the cellulose ester composition includes a celluloseester and a plasticizer. In embodiments, the cellulose ester iscellulose acetate and the plasticizer is triacetin.

A method of forcing a disassembly of a GRDF within a patient is providedin accordance with the present disclosure that includes: administering aGRDF to a patient; and administering an antidote to the patient, whereinthe antidote increases a pH of the patient's stomach forcing the GRDF todisassemble into pieces of sufficient size to evacuate the stomach.

In embodiments, the GRDF includes a body comprising a pH sensitivematerial which represents less than about 20% of a total weight of thebody, wherein the pH sensitive material is configured to force the GRDFto disassemble.

The present disclosure also includes the use of an immediate releaseformulation in the manufacture of a GRDF is provided. In embodiments,the formulation is an insert (tablet).

A controlled release formulation is provided in accordance with thepresent disclosure that includes a body including a cavity suitable forretaining an API composition, wherein the body defines a surface area ofexposure of the API composition which allows for the controlled releaseof the API.

In embodiments, the API is released over more than 4 hours, in aspects,over more than 8 hours, in aspects, over more than 12 hours, in aspects,over more than 18 hours, in aspects, over more than 24 hours.

While several embodiments of the disclosure have been shown in thedrawings, it is not intended that the disclosure be limited thereto, asit is intended that the disclosure be as broad in scope as the art willallow and that the specification be read likewise. Therefore, the abovedescription should not be construed as limiting, but merely asexemplifications of particular embodiments. Those skilled in the artwill envision other modifications within the scope and spirit of theclaims appended hereto.

EXAMPLES Example 1—Preparation of GRDF

A. Preparation of Hot Melt Extrudant (HME)

Seven hot melt extrudants were prepared according to parametersdescribed in Table 1.

TABLE 1 Preparation on Extrudants in HME Machine Polymer: Pre-Mixing Hotmelt HME HME Extrudant Plasticizer time (min, Hold flow rate temp RPMMilled No. Polymer Plasticizer Ratio RPM) time 1 kg/hr {° C.] snailpellets 1 HPMC Acetate Triethyl  4:1 5 min, 24 hr 1 170 100 1.5 mmsuccinate HG citrate 500 RPM 2 HPMC Acetate PEG 3350  8:1 5 min, 24 hr 1170 100 1.5 mm succinate 500 RPM 3 Cellulose acetate Triacetin  4:1 2-5min, 24 hr 1 190 100 1.5 mm 500 RPM 4 ETHOCEL ® 7CP Triethyl  4:1 5 min,24 hr 1 160 100 1.5 mm citrate 500 RPM 5 EUDRAGIT ® S Triethyl  4:1 5min, 24 hr 1 150 100 1.5 mm citrate 500 RPM 6 HPMC Acetate Triethyl 12:12 min, 24 hr 1 170 100 1.5 mm succinate HG:MG citrate 500 RPM 1:4 7Cellulose acetate Triethyl  5:1 2 min, 24 hr 1 160 100 1.5 mm KLUCEL ®10:1 citrate 500 RPM

Specifically, with reference to Extrudant No. 3, the materials loadedinto the injection molding machine were prepared by the followingsequential steps:

-   -   1. The polymer (e.g. cellulose acetate 0.5 kg) was premixed with        the plasticizer (e.g. Triacetine 0.125 kg) in DIOSNA mixer (6 L)        for 5 min, 500 RPM.    -   2. After premixing, the mixture was place at room temperature        for 24 hr so that the polymer and plasticizer settled together.    -   3. After 24 hr the mixture was fed into the HME machine (e.g. by        a gravimetric feeder at 1 kg/hr rate).    -   4. The HME machine was pre-heated to the defined temperature        (e.g. 190° C. for Extrudent No. 3 in Table 1).    -   5. The HME snail speed was set to 100 RPM.    -   6. While the HME machine was fed with the material, a vacuum        system attached to the HME machine was activated to enable        drawing any water in the mixture.    -   7. As the melted material was drawn from the HME machine it was        forwarded as strands onto a conveyor belt and cooled. Once        cooled, the strand was chopped by a chopping machine to        particles of about 1.5-2 mm size.    -   8. After chopping, the material was dried under vacuum at 50° C.        for 5 hr to enable water evaporation (loss on drying was        recorded at below 1%).

B. Preparation of GRDF Mold Via Injection Molding

The relevant mold tool was placed in a suitable injection moldingmachine. The hot melt extrudants were applied to an injection moldingmachine (Wittman EcoPower 55 Ton Injection Molding Machine) andinjection molded, as described above, while using the parameters listedin Table 2.

TABLE 2 Extrudant Screw Nozzle Ejection Mold Cycle Formulation No. fromExtrusion speed temp pressure temp time No. Table 1 Polymer Plasticizertemp [° C.] [rpm] [° C.] [kg/cm2 [° C.]l [sec] 1 1 HMPC Triethyl 175-190200 210 1200 40 17 Acetate citrate succinate HG 2 2 HMPC PEG 3350150-180 200 185 1200 40 18 Acetate succinate 3 3 Cellulose Triacetin 180to 200 250 230 1600 45 18 acetate 4 4 ETHOCEL ® Triethyl 160-175 250 1801000 50 30 7CP citrate 5 5 EUDRAGIT ® Triethyl 160-200 250 210 1600 5020 S citrate 6 6 HMPC Triethyl 175-190 200 210 1200 40 17 Acetatecitrate succinate HG:MG 1:4 7 7 Cellulose Triethyl 180 to 200 250 2301600 45 18 acetate citrate KLUCEL ® 10:1

C. Preparation of the Insert Tablets

Punches according to the insert were prepared and include the dimensionsdepicted in FIG. 54.

Internal granulation ingredients were mixed thoroughly in a Ycone mixerfor 5 minutes. After mixing, the ingredients were wet granulated withcold water in a diosna mixer. The granulate obtained was dried in afluid bed drier (FBD). Later, the granulate was milled in a Erwekamilling machine. After milling, extra-granulate ingredients were addedand thoroughly mixed in the Ycone mixer for 5 minutes. The final blendobtained was compressed to tablets using a Bonapache D compressingmachine having a 22.5×9.0 mm die. Hardness of 20 SCU was obtained.Alternatively, the final blend was compressed manually using a SPECACcompressing unit having a 2 ton force and a 6×12.5 mm die. Thecomposition of each insert is shown in Table 3.

TABLE 3 Insert Insert Insert Insert Tablet 1 Tablet 2 Tablet 3 Tablet 4mg mg mg mg Internal Granulation API 500 370 370 370 HPMC E4M 13 6.6 9.79.7 Starch 1500 180 20 20 20 Wet granulation Water (cold) ExtragranulateAVICEL ® 102 100 23.4 28.3 31 MgS 7 4 4 4 Sodium starch glycolate 16 85.3 Total Weight 800 440 440 440

The insert was compressed using a conventional press machine to obtaintablets with a size which matches the inner side of the arms (preparedby injection molding, as described above). The distance from the insertouter surface to the inner surface of the arms wall was about 5 to 150microns to enable proper insertion. The final adjustment of the insertsize was completed by adjustment of the insert weight and thecompression force.

D. Assembly of the GRDF

Insert tablet 1 was inserted into each of the two arms prepared fromFormulation No. 3 (see Table 2) with a variety of insert tablet surfacearea exposure as in Table 4. The hinge and the arms were assembled bypushing the hinge into the arms. The obtained assembled unit wascollapsed (i.e., FIG. 33 for example) and inserted into a 000 gelatinecapsule, e.g., CAPSUGEL® (See FIG. 16 for example) and subjected todissolution trials, as described below.

Example 2—Dissolution Study 1

Each assembled GRDF was placed in a Rotating apparatus [VANKEL ROTATINGBOTTLE apparatus (VARIAN)] and subjected to dissolution and emptyingtests. 500 ml dissolution chamber bottle was used with 400 ml HCL 0.1Nat 37° C. and 150 grams of glass beads. The dissolution chamber wasrotated at 8 RPM. 5 ml samples were taken after 1, 2, 3, 5, 6, and 24hours to measure API release rate.

TABLE 4 Sample 1 Sample 2 Sample 3 Sample 4 Formulation Insert InsertInsert Insert tablet 1 tablet 1 tablet 1 tablet 1 [above] [above][above] [above] Injection Extrudant 3 Extrudant 3 Extrudant 3 noneMolded Mold IM Release Front- Front- Front + Deck- none area see FIG.see FIG. see FIG. Presence of No beads 150 g beads 150 g beads 150 gbeads beads

The results of the dissolution tests are shown in FIG. 37. In summary:

-   -   1. Sample 1 resulted in an extended release profile of up to 24        hr.    -   2. Sample 2 (wherein glass beads provided an increase in        mechanical effect on the GRDF) resulted in a moderate increase        in release profile but with no dose dumping effect.    -   3. Sample 3, having more release holes than Sample 2 (front and        deck openings), resulted in an increase in release profile.    -   4. Sample 4 (insert only, not contained in arms) resulted in a        release profile which was very fast—100% within 1 hr.

Example 3-17.5 mm Pipe Test

A 17.5 mm pipe test was performed on Sample 2 (See Table 4) to simulateexit of the GRDF components from the stomach. The pipe test was done atT=0, T=10 hr and T=24 hr. A standard bottle head was switched to a pipehaving a diameter of 17.5 mm and a length of 5 cm. Content was testedfor capacity to exit the bottle by manual shaking in an upside-downposition.

TABLE 5 Pipe test results of standard extended release (“ER”) tablet(Insert) T = 0 T = 10 hr T = 24 hr Standard ER Exited pipe Exited pipeExited pipe Tablet Sample 2 Remained in Remained in pipe, Exited pipe,insert (See Table 4) pipe insert tablet 80% tablet eroded eroded

Example 4A: Dissolution Test 2

Samples described in Table 5A below were placed in 500 ml dissolutionchamber bottle (described above) where 400 ml with solution of HCL 0.1Nor buffer acetate pH 4.5 at 37° C. and with or without 150 grams ofglass beads which were added beforehand. The dissolution chamber wasrotated in 8 RPM. 5 ml samples were taken after 1, 2, 3, 5, 6 and 24hours to measure API release rate.

TABLE 5A Example 4a Example 4b Example 4c Example 4d FormulationStandard Standard See Sample See Sample ER tablet ER tablet 2 2 IM partnone none See Sample See Sample 2 2 IM release area none none FrontFront Dissolution No beads 150 g beads No beads 150 g beads mechanics bypH 1 1 1 1The results of this dissolution test are shown in FIG. 38. In summary:

-   -   1. Sample 4c resulted in an extended release profile of up to 12        hr.    -   2. Sample 4d resulted in a moderate increase in release profile        with no dose dumping effect.    -   3. Samples 4a and 4b (i.e., standard ER tablet) resulted in        complete release within 4 hr, independent of increased        mechanical force applied by the glass beads.

Example 5A—Preparation of GRDF

Two GRDF configurations were made, both with the same insert formulation(see Table 6 below); Configuration 1 was made from erodible, pHdependent, injection molding parts and Configuration 2 was made fromharder, non pH dependent, injection molding parts. The “inserts” wereinserted into two each of the two arms (1 & 2) according to Table 6below. The hinge assembly and the arms were assembled by pushing thehinge assembly into the arms, e.g., see FIG. 34A. The obtained assembledunit was closed and inserted into a 000 gelatine capsule (CAPSUGEL®) andsubjected to dissolution trials, as described below.

TABLE 6 Configuration 1 Configuration 2 IM parts erodible, pH nonerodible, non pH dependent dependent T arm * Extrudant 6 Extrudant 3HPMC CA:triacetin 4:1 HG:MG:Triacetin 9:3:1.2 S arm * Extrudant 7Extrudant 7 CA:Triacetin:klucel CA:Triacetin:klucel 10:2:1 10:2:1 Thinge * Extrudant 3 Extrudant 3 CA:triacetin 4:1 CA:triacetin 4:1 Shinge* Extrudant 7 Extrudant 3 CA:Triacetin:klucel CA:triacetin 4:110:2:1 Formulation T arm Insert 2 Insert 3 formulation ** S arm Insert 2Insert 3 formulation ** * See Table 2 above ** See Table 3 above

Example 5B—Dissolution Study 3

The two assembled GRDF configurations were placed in the Rotatingapparatus [VANKEL ROTATING BOTTLE apparatus (VARIAN)] and subjected todissolution and emptying tests. 500 ml dissolution chamber bottle wasused (described herein) with 400 ml HCL 0.01N (pH 2) or with bufferacetate (pH 4.5) at 37° C. The dissolution chamber was rotated at 8 RPM.5 ml Samples were taken after 0.5, 1.5, 2.5, 4, 5.5, 8, and 22 hr tomeasure API release rate. After 4 hr the sampling medium was switchedwith fresh medium. The disassembly of the GRDF was also monitored(disassembled parts tested for passage through a pipe test tube as anindicator for gastric emptying as described herein). Unfolding time forthe GRDF was monitored. Following 22 hr of exposure of Configuration 1to pH 2, the medium was switched to buffer phosphate pH 6.5 to testerosion/dissolution time of the GRDF components.

At T=0, the GRDFs were inserted into the rotating apparatus in thecollapsed configuration contained within a capsule. At T=5 min, allcapsules were dissolved and the GRDFs were unfolded. The results of thisdissolution and disassembly study are shown in FIG. 39.

In Summary:

-   -   1. No significant difference in unfolding time, release profile,        or disassembly time were observed for both configurations.    -   2. Unfolding was achieved in all cases in less than 5 minutes.    -   3. Near Zero order profile of about 8 hr was obtained.    -   4. The release profile was not affected significantly by pH        alteration (pH 2.5 vs pH 4.5)    -   5. Disassembly took place after more than 8 hr, at which point        more than 85% of the API was released.    -   6. pH dependent parts were eroded and dissolved completely        within 5 hours.    -   7. pH dependent parts were eroded and dissolved completely        within 5 hours.

Example 6: Openings and Formulation Effect on Release Profile

a. Formation of GRDF Mold:

-   -   Formulation 3 from Example 1B was used to produce molds in FIGS.        34B and 35 where two parallel lines of equal number of holes run        from tip to hinge along the arm.    -   b. Preparation of Insert

Insert composition is shown in Table 7 below.

TABLE 7 Configuration 1 Configuration 2 insert tab A insert tab B[delete in final: R- [delete in final: R- Ingredients 11529] 11750A]internal gran A API 370 370 HPMC E4M 9.7 8 Starch 1500 20 20extragranulate avicel 102 28.3 22 SSG (sod. Starch glyc) 8 16 MgS 4 4Total weight 440 440

Internal granulation ingredients were mixed thoroughly in a Ycone mixerfor 5 minutes. After mixing, the ingredients were wet granulated withcold water in a diosna mixer. The granulate obtained was dried in afluid bed drier (FBD). Later, the granulate was milled in a Erwekamilling machine. After milling, extra-granulate ingredients were addedand thoroughly mixed in the Ycone mixer for 5 minutes. The final blendobtained was compressed to tablets using a Bonapache D compressingmachine having a 22.5×9.0 mm die. Hardness of 10 SCU was obtained.Alternatively, the final blend was compressed manually using a SPECACcompressing unit having a 2 ton force and a 6×12.5 mm die.

Punches according to the insert of the tablet were prepared with thedimensions (in millimeters) as shown in FIG. 54.

The insert in FIG. 26 was compressed using a conventional press machineto obtain inserts tablets. The insert tablet was inserted into thecavity of the arm mold (as exemplified in FIG. 28-31) which on assemblywas sandwiched between the hinge and the arm mold. To enable smoothinsertion, a tolerance (gap) between the insert outer surface to theinner surface of the arm mold was set to about 50 to 150 μm. Inaddition, a final adjustment of the insert size dimensions to enablesmooth insertion was done through tablet compression by adjustment ofthe insert weight and the compression force.

a. Assembly of the GRDF

As shown in FIG. 18, one insert was inserted into each of the two arms.The hinge assembly, hinge assembly 66, and the arms, e.g., arms 62 and64 were assembled by pushing the hinge assembly 66 into respectivecavities 62′ and 64′ between the insert and the hinge assembly 66.

TABLE 8 Assembled units configurations before test Mold innerformulation mold holes size HPMC Mold diameter, number E4M samplecomposition of holes SSG (MET) 1 CA no holes Insert Tab A 1.8 2.2Triacetine 4:1 2 CA 1.4 mm, 4 holes Insert Tab A 1.8 2.2 Triacetine 4:13 CA 2 mm, 10 holes Insert Tab A 1.8 2.2 Triacetine 4:1 4 CA no holesInsert Tab B 3.6 1.8 Triacetine 4:1ine 5 CA 2 mm, 10 holes Insert Tab B3.6 1.8 Triacetine 4:1

The Assembled product is shown in FIG. 34B

b. Dissolution Study

The two assembled GRDF configurations were placed in the Rotatingapparatus [VANKEL ROTATING BOTTLE apparatus (VARIAN)] and subjected todissolution and emptying tests. A 500 ml dissolution chamber bottle wasused with 400 ml HCL 0.01N (pH 2) or with buffer acetate (pH 4.5) at 37°C. The dissolution chamber rotated in 8 RPM. 5 ml Samples were takenafter 0.5, 1.5, 2.5, 4, 5.5, 8 and 22 hrs to measure API release rate.After 4 hrs, sampling medium was switch with new fresh medium.

Results:

-   -   a. Dissolution profile and disassembly time is shown in FIG. 52.

Conclusions:

-   -   a. There was no significant difference in expanding time.        Unfolding was achieved with <3 min    -   b. Disassembly consistently occurred at about 80% API release    -   c. Disassembly could be shifted between about 7 hrs and at least        24 hrs by modifying holes and excipients.        -   1. Mold external surface area: Increasing the diameter of            the holes resulted in a faster profile        -   2. Increasing the disintegrant while lowering the matrix            polymer (MET) resulted in an increased profile

Example 7: An 18 mm Pipe Test for Simulating Gastric Retention Under anApplied Force

a. Assembly of a GRDF

The molded parts, i.e., the arms, hinge assembly, and biasing element(e.g., leaf spring), of the GRDF were made of Cellulose Acetate (CA) andTriacetin combined in a 4:1 ratio, respectively. (See, Formulation No. 3from Table 2)

Insert No. 4 was placed into each of the molded arms made from theformulation provided in Table 3. Then the arms were combined with thehinges to form a fully assembled GRDF.

b. Experiment 1—GRDF Exposure to Gastric Simulated Conditions Prior toPIPE Test (Test Done in Triplicates)

The fully assembled GRDF was placed in simulated gastric conditionsi.e., at 37° C., pH2+Xanthan gum 0.125 gr/L, 25 RPM mixing. In thismodel, the formulation obtained a near zero order release profile for 20hr. At T=0, 1, 3, 6, 9, 24 hr the product was taken out of the rotatingapparatus and immediately subjected to a second Pipe test as describedbelow to evaluate the 24 hr durability of the GRDF to resist passingthrough the pipe.

c. Experiment 2—Second [18 mm] Pipe Test Apparatus

The scheme of the 18 mm pipe test is depicted in FIGS. 40A and 40B. Thedimensions are further described below in Table 9. In short, an adaptorwas attached to a texture analyzer HD purchased from Stable Microsystem,Corp. A 5 kg load cell was used for the test.

In each interval (T=0, 1, 3, 6, 9, and 24 hr), the GRDF was extractedout of the dissolution apparatus and placed in the pipe container in 3orientations (A, B, and C) as illustrated in FIG. 40B. In eachorientation, a force of 600 grF was applied 10 times at a speed of 10mm/sec (by the adaptor descending and ascending). In the last interval,the adaptor was forced to descend through the pipe so to measure themaximal force needed for the GRDF to pass through the pipe or to breakinto parts. In addition, the GRDF was randomly thrown gently into thepipe container 10 different times, and each time exposed to the sameforce, as provided above. The results are given below.

TABLE 9 # Description Dimension (mm) A Pipe height 30 B Pipe passkeydiameter 18 C Pipe Passkey edge 4 D Cone height 45 E Cylinder height 60F Cylinder diameter 70 G Adaptor cone base diameter 60 H Adaptor leadheight 30 I Adaptor lead diameter 15 J Adaptor coned 40

Test Results

The test results are described in Table 10 below. Some specific resultsinclude the following:

-   -   1. Insert erosion was near a zero order rate (visual observation        of material remained)    -   2. The sample GRDFs endured mechanical forces of up to 3000 grF        after 24 hr without significant deformation. (at orientation B,        C, and D)    -   3. The sample GRDFs disassembled under the application of 400        grF, when positioned in orientation D, at 24 hr, and as the        insert almost completely eroded.

TABLE 10 % insert tab remaining Forced Did part retain on pipe or passthrough it? grForce (visual applied Orientation time observation)grFroce A B C D (random) comment 0 100 600 did not pass did not pass didnot pass did not pass mold remained intact through pipe through pipethrough pipe through pipe 1 95 600 did not pass did not pass did notpass did not pass mold remained intact through pipe through pipe throughpipe through pipe 3 90 600 did not pass did not pass did not pass didnot pass mold remained intact through pipe through pipe through pipethrough pipe 6 80 600 did not pass did not pass did not pass did notpass mold remained intact through pipe through pipe through pipe throughpipe 9 70 600 did not pass did not pass did not pass did not pass moldremained intact through pipe through pipe through pipe through pipe 2410 300 did not pass did not pass did not pass passed* mold remainedintact through pipe through pipe through pipe 24 10 400-3000 passed* didnot pass did not pass passed* through pipe through pipe *partsdisassembled.d. Experiment 3: In Vitro Leaf Spring Durability Test

The expanded configuration of the GRDFs described herein is highlydependent on the biasing mechanism or leaf spring durability whensubjected to mechanical forces, e.g. compression that might occur in thestomach. Such forces might cause downsizing and/or folding of the GRDFresulting in premature emptying from the stomach and insufficientgastric retention.

The leaf spring durability test was used to evaluate the degree ofdeformation of the GRDF in response to increasing compression forcesapplied thereto. The compression forces were applied as described below.

The sample GDRF was tested at T=0 and immediately after exposure tosimulated gastric fluids—5 RPM Rotating apparatus having 37° C., Xanthangum [0.125 gr/L pH2] with 25 RPM mixing for 12 hrs.

The sample GDRF was attached to a holder (keeping the sample GDRFstagnant). The holder was placed below the Texture analyzer (StableMicrosystem, Corp.). As illustrated in FIG. 41, a probe was attached toa load cell of 5 kgF. Thereafter, the probe descended upon the sampleGDRF and contacted the sample GRDF (trigger force of 20 gr) whiledescending, the force derived and the change in probe position wererecorded by the load cell. After reaching the defined force the probeascended back to the start position. This cycle was applied 30 timeswith a 5 second recovery in between cycles. The GRDF compression modulus(gr/mm) as well as plasticity after 30 cycles were calculated (see FIGS.42 and 43 and Table 11 below)

Test Results:

The test results are described in Table 11 below. Some specific resultsinclude the following:

-   -   1. At t=0 and after 12 hr of exposure to simulated gastric        fluids the GRDF had 3% plastic deformation (plasticity) after 30        cycles.    -   2. At t=0 the GRDF 350 grF compression resulted in less than 6%        deformation. Calculated compression modulus was 175 gr/mm.    -   3. Only by applying 1250 grF did the GRDF have significant        plastic deformation (marked in FIGS. 42 and 43)

TABLE 11 Maximum Maximum % deformation % change in change in(plasticity) height during height during compression % change compare toexposure time Force compression compression modulus T = 0 in initialheight to simulation applied after cycle 1 after cycle 1 after cycle 1at cycle 30 alter 5 gastric fluids [grams] [mm] [%] (gr/mm) sec recovery0 hr (T = 0) 350 15 5.8 175 0.0 750 5 19.2 150 −1.9 1250 12 46.2 N/A−15.4 12 hr 750 6 23.1 170 −3.0e. Experiment 4—PIG Study—Time Until the GDRF Opens and Safety andDurability of the GRDF

Three (3) pigs were given the GRDF which included an insert tablet madeaccording to the formulation provided in Table 12 below. The GRDF wasthen encapsulated within a gelatin capsule 000* (CAPSUGEL®). As the GRDFwas 28 mm in length, the size 000 gelatin capsule was not fully locked.

TABLE 12 batch R-11206 detail tablet preparation by mixing folowed bydirect compression ingredients mg/tab Ethocel 7CPS 158.4 HPMC E4M 13.2Starch 1500 88 Lactose SD 158.4 SSG (sod. Starch glyc) 4.4 MgS 17.6Total Weight 440

The study was conducted in the LAHAV research institute (Israel). Eachof the pigs were anesthetized (short term 10 min anesthesia) and given200 ml at 37° C. After 5 minutes, the pigs were administered the GRDF.Endoscope testing was performed at T=4.5 hr, 9 hr, and 24 hrs.

Test Results:

Some specific test results included the following:

-   -   1. The rapid unfolding of the product was visualized by        endoscope <5 min after administration. See FIG. 44 which shows        the GRDF in an unfolded configuration at t=5 min positioned        within the pig stomach.    -   2. The insert eroded gradually from T=0 to 24 hr while the outer        portion of the GRDF was maintained.    -   3. The endoscope pictures provided in FIGS. 44 and 45        exemplified that no significant visualized deformation of the        GRDF occurred.    -   4. The integrity of the stomach tissue was explored by the        veterinarian during each endoscope imaging. The veterinarian        concluded that no tissue damage was observed. Animal behavior,        food consumption as well as feces were found normal.        f. Experiment 5—Dog Study in Beagle

The goal of the study was to evaluate the performance of the GRDF in adog, such as a beagle. The following were evaluated:

-   -   1. GRDF opening in the stomach    -   2. Gastric retention of the GRDF    -   3. Safety (visual observation of feces, and dog behavior)        Two GRDF samples were chosen having two different release        profiles in vitro (see below) by modifying the surface area of        the mold holes, as seen in FIGS. 48-51.        a. Sample GRDF Preparation

The two GRDFs were prepared as described in Example 4 with a fewmodifications.

-   -   1. Holes were made in each arm by manual drill.        -   a. Sample A—4 holes of 1 mm        -   b. Sample B—10 holes of 1.2 mm—[SS]— TABLE 13 says 10 holes    -   2. A radio-opaque thread was attached to each arm by filing a        small cut in mold and gluing the thread with a glue made of 3%        cellulose acetate in acetone and left to dry for 10 minutes.        FIG. 46 depicts a GRDF having radio opaque threads attached        thereto (Shown in photo as black lines).        b. In Vitro Dissolution and Test Results

TABLE 13 % erosion-visual observation′ erosion rate Disassembly batch 03.5 8 10 12 22 40 (%/hr) hr Sample A - 1 mm 0% 25% 45% 55%  60%  93%100% 4.1%  8-12 hr holes × 4 Sample B - 1.2 mm 0% 30% 65% 80% 100% 100%100% 8.2% 16-20 hr holes × 10

The assembled GRDF dissolution was tested under simulated gastricconditions 5 RPM Rotating apparatus having 37° C., Xanthan gum [0.125gr/L pH2] with 25 RPM mixing. At each interval, the sample GRDF wasextracted and the erosion of the insert was visually estimated. Thestate of disassembly of the GRDF was also evaluated. Work was done induplicates for each of the samples. The results are described in Table13 and shown in FIGS. 46 and 47. Disassembly occurred when less than 20%of the insert remained. Sample A which had a reduced surface area ofinsert exposure displayed a slower release profile than Sample B.

c. Imaging Study

Beagle dogs (9-10 kg weight, age 6 months) were fasted for 12 hrs priorto and after the administering of the GRDF. Six (6) dogs received SampleA with 5 mm barium impregnated polyethylene spheres (BIPS) meant as acontrol to observe gastric emptying rate and the intestinal transit timeof food. Three (3) dogs received Sample B with control.

The samples were administered utilizing endoscopic device directly intothe stomach of lightly anesthetized dogs after administration ofpre-warmed water 75-100 cc water. The dogs were fed a 300 gr meal at 12hours post dose administration. The dosing was repeated in a cross overmanner.

The gastric retention was evaluated by Siemens fluoroscopic x-rayimaging that visualized the exact placement of the radiopaque labeledtest article and the BIPS, performed at several times. FIGS. 48 to 51illustrate the gastric retention of the GRDF and the BIPS at 4 hr, 8 hr,12 hr, and 24 hr intervals, respectively. Animal behavior and fecestexture were recorded.

In all dogs, the GRDF expanded in the stomach. The percentage of dogsexhibiting gastric retention is provided in Table 14 below. Note thatadjusting the dissolution profile of insert results in the extent ofgastric retention.

TABLE 14 % of dogs exhibiting gastric retention of GRDF Sample # of dogs4 hr 8 hr 12 hr 16 hr 24 hr 30 hr 40 hr beads 7 100% 17%  0%  0%  0%  0%0% Sample A 6 100% 50% 50% 50% 50% 50% 0% Sample B 3 100% 66%  0%  0% 0%  0% 0%

As seen in FIGS. 48-51 and Table 14 above, the emptying of the control,i.e., beads, was complete after about 8 hr while Sample A remained inthe dog stomach for at least 24 hrs.

FIGS. 53A-53D show ingestion through disassembly schematic illustrationsof a GRDF according to any of the embodiments described herein. During afirst stage as shown in FIG. 53A, the GRDF is encapsulated within aretentions mechanism, e.g., capsule 20. After ingestion and after aperiod of about 1 minute to about 10 minutes, the retention mechanismdissolves allowing the GRDF to expand from a collapsed configuration(FIG. 53B) to an expanded configuration (FIG. 53C) which prevents theGRDF from passing through the pyloric valve of the stomach. Inembodiment, the smallest length of the arms and the distance between thetips of the arms to sustain retention is about 26 mm. Over a nextpredetermined period of time API or diagnostic is released in any of themanners described herein. After a predetermined period of time (asdescribed herein) or upon a sufficient amount of API being released (asdescribed herein) or upon the occurrence of a mechanical event (asdescribed herein), the GRDF disassembles for passage through the pyloricvalve.

What is claimed:
 1. A gastroretentive dosage form (GRDF) for retentionin a stomach, comprising: a hinge assembly; two parts connected togetherby the hinge assembly; and a composition comprising an activepharmaceutical ingredient (API) or diagnostic, wherein the hingeassembly and the two parts are configured to transform between acollapsed configuration for ingestion, an expanded configuration forretention within the stomach, and a third configuration wherein at leastone of the two parts disengages from the hinge assembly, wherein saiddisengagement is due to at least partial erosion of the composition, andwherein the disengaged parts are sized for exiting the stomach throughthe pyloric valve.
 2. The GRDF of claim 1, wherein the two parts are twoarms.
 3. The GRDF of claim 1, wherein the two parts are pivotablyconnected to each other by the hinge assembly.
 4. The GRDF of claim 1,wherein the two parts comprise a pH dependent polymer that erodes in abasic environment.
 5. The GRDF of claim 1, wherein the two parts areerodible at a pH of 5 to 7.5.
 6. The GRDF of claim 1, wherein the atleast one of the two parts comprises a cellulose ester and aplasticizer.
 7. The GRDF of claim 6, wherein the cellulose ester iscellulose acetate, cellulose triacetate, hydroxypropylmethylcelluloseacetate succinate, cellulose proprionate, cellulose acetate proprionate,cellulose acetate butyrate, or a combination thereof.
 8. The GRDF ofclaim 6, wherein the plasticizer is dibutyl sebacate, triethyl citrate,polyethylene glycol, polyethylene glycol monomethyl ether, acetyl tributyl citrate, triacetin, or a combination thereof.
 9. The GRDF of claim1, comprising a volume for engaging the composition ranging from about100 mm3 to about 2000 mm3.
 10. The GRDF of claim 1, wherein the partialerosion of the composition occurs after a predetermined time period ofat least four hours has elapsed, preferably the predetermined timeperiod is at least 12 hours.
 11. The GRDF of claim 1, wherein thedisengagement is due to erosion of greater than 50% of the API or thediagnostic from the GRDF.
 12. The GRDF of claim 1, wherein the API orthe diagnostic erodes at a controlled rate over more than 6 hours. 13.The GRDF of claim 1, wherein the GRDF is maintained in the collapsedconfiguration by a retention mechanism that dissolves when introduced toa fluid environment and wherein said GRDF transitions to the expandedconfiguration upon at least partial dissolution of said retentionmechanism in less than 5 minutes.
 14. The GRDF of claim 1, wherein thecomposition further comprises an excipient, and wherein a ratio of theweight of the excipient to the weight of the API or the diagnostic isfrom about 0.8 to about 0.05.
 15. The GRDF of claim 1, furthercomprising a second API or a second diagnostic.
 16. The GRDF of claim 1,wherein the parts are produced by injection molding or 3D printing. 17.The GRDF of claim 1, wherein the composition is retained in the stomachfor a time period of more than 6 hours.
 18. The GRDF of claim 1, whereina size, shape, or durability of each of the two parts is substantiallymaintained prior to their disengagement.
 19. The GRDF of claim 1,further comprising a biasing element configured to transition the GRDFfrom the collapsed configuration to the expanded configuration.
 20. TheGRDF of claim 1, having a mechanical durability to remain intact under arepeated force of at least about 400 grF, for a time period of at least1 hour.